A Phase 1/2, Randomized, Observer-Blind, Dose-Finding, Controlled, Parallel-Group, Two-Stage Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of a 24-Valent Pneumococcal Conjugate Vaccine (VAX-24) in Healthy Adults Aged 18 to 64 Years
Phase: PHASE1
Conditions: Pneumococcal Vaccines
Sponsor: Vaxcyte, Inc.

VAX24-101 
 
 
CLINICAL STUDY PROTOCOL:  A Phase 1/2a, Randomized, Observer-Blind, Dose-
Finding, Controlled, Parallel-Group, Two-Stage 
Clinical Study to Evaluate the Safety, Tolerability, 
and Immunogenicity of a 24-Valent Pneumococcal 
Conjugate Vaccine (VAX-24) in Healthy Adults 
Aged 18 to 64 Years 
  
 
 
NCT IDENTIFIER:    
 
NCT05266456 
 
DOCUMENT DATE:   
 
31 May 2022 

CLINICAL STUDY PROTOCOL 
PROTOCOL TITLE: 
A Phase 1/2a, Randomized, Observer-Blind, Dose-Finding, 
Controlled, Parallel-Group, Two-Stage Clinical Study to Evaluate 
the Safety, Tolerability, and Immunogenicity of a 24-Valent 
Pneumococcal Conjugate Vaccine (VAX-24) in Healthy Adults 
Aged 18 to 64 Years 
PROTOCOL NUMBER: 
VAX24-101 
INVESTIGATIONAL 
PRODUCT: 
SPONSOR: 
VERSION: 
DATE: 
VAX-24 
(24-valent Pneumococcal Conjugate Vaccine) 
Vaxcyte, Inc. 
825 Industrial Road 
Suite 300 
San Carlos, CA 94070 USA 
Tel: 650 837 0111 
4.0 
31 May 2022 

Protocol VAX24-101, V4.0, 31-May-2022 
VAX-24; Vaxcyte, Inc. 
Page 2 of 67 
 
 
 

Protocol VAX24-101, V4.0, 31-May-2022 
VAX-24; Vaxcyte, Inc. 
Page 3 of 67 
 
 
 
PROTOCOL SIGNATURE PAGE 
 
Protocol Number VAX24-101 
(Version 4.0) 
This Clinical Study Protocol document and all information provided to you, the Principal 
Investigator, related to this protocol are the confidential and proprietary information of Vaxcyte, 
Inc. (“Sponsor”) and are subject to the terms of the Confidential Disclosure Agreement between 
you and Vaxcyte, Inc. 
 
 
By signing below, I hereby confirm the following: 
I agree to abide by the terms of the Vaxcyte, Inc. Confidential Disclosure Agreement. 
I have read this protocol entitled, “A Phase 1/2a, Randomized, Observer-Blind, Dose-Finding, 
Controlled, Parallel-Group, Two-Stage Clinical Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of a 24-Valent Pneumococcal Conjugate Vaccine (VAX-24) in Healthy Adults 
Aged 18 to 64 Years” in its entirety and I agree to conduct the study according to this protocol. 
Any changes in procedure will only be made if necessary to protect the safety, rights, or welfare 
of subjects. 
I agree to comply with the current International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice in addition to the appropriate FDA Code of Federal 
Regulations (CFRs) and applicable state and local regulations. 
I agree to conduct the study in person or to supervise the study. 
I agree to ensure that all who assist me in the conduct of the study have access to the study 
protocol, including any amendments thereto, and are also made aware of their responsibilities in 
meeting the foregoing obligations. 
 
 
 
Principal Investigator 
(Print Name) 
 
 
 
 
Title 
 
 
 
 
Signature 
Date 
 
Site to send signed copy to Vaxcyte, Inc. and to keep original for files. 

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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ......................................................................................... 1 
VAXCYTE APPROVALS ....................................................................................................... 2 
PROTOCOL SIGNATURE PAGE ........................................................................................ 3 
TABLE OF CONTENTS ......................................................................................................... 4 
LIST OF TABLES ................................................................................................................... 8 
LIST OF FIGURES ................................................................................................................. 8 
LIST OF ABBREVIATIONS .................................................................................................. 9 
PROTOCOL SYNOPSIS ...................................................................................................... 11 
1 
INTRODUCTION ...................................................................................................... 14 
1.1 
Background and Rationale ............................................................................... 14 
1.2 
Name and Description of Investigational Vaccine ........................................... 16 
 
 
 
 
 
 
 
 
1.2.2 
Rationale for Dosage and Route of Administration .......................... 19 
2 
OBJECTIVES AND ENDPOINTS ........................................................................... 20 
2.1 
Primary ............................................................................................................. 20 
2.2 
Secondary ......................................................................................................... 20 
 
 
3 
STUDY PLAN ............................................................................................................ 22 
3.1 
Study Design .................................................................................................... 22 
3.2 
Number of Study Participants .......................................................................... 23 
3.3 
Estimated Study Duration ................................................................................ 23 
3.4 
Study Population .............................................................................................. 24 
3.4.1 
Inclusion Criteria ............................................................................... 24 
3.4.2 
Exclusion Criteria .............................................................................. 25 
4 
STUDY VACCINE ..................................................................................................... 27 
4.1 
Investigational Vaccine (VAX-24) .................................................................. 27 
4.1.1 
Active Comparator ............................................................................ 27 
4.1.2 
Other Supplies ................................................................................... 28 

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4.2 
Dose Preparation of Study Vaccines ................................................................ 28 
4.3 
Accountability Procedures for Study Vaccines ................................................ 29 
5 
STUDY PROCEDURES ............................................................................................ 30 
5.1 
Informed Consent ............................................................................................. 30 
5.2 
Screening .......................................................................................................... 30 
5.3 
Medical History ................................................................................................ 31 
5.4 
Physical Examination ....................................................................................... 31 
5.5 
Vital Signs ........................................................................................................ 32 
5.6 
Laboratory Tests ............................................................................................... 32 
5.6.1 
Blood Volume ................................................................................... 32 
5.6.2 
Safety Laboratory Assessments......................................................... 34 
5.6.3 
Immune Response Assessments ........................................................ 35 
5.7 
Pregnancy Testing and Contraception .............................................................. 35 
5.8 
Randomization.................................................................................................. 36 
5.9 
Study Vaccine Administration ......................................................................... 37 
5.10 
Acute Observation ............................................................................................ 37 
5.11 
Solicited Adverse Events ................................................................................. 37 
5.12 
Unsolicited Adverse Events ............................................................................. 38 
5.13 
Prior and Concomitant Medications and Procedures ....................................... 38 
5.14 
Prohibited Medications and Therapies ............................................................. 38 
5.15 
Emergency Unblinding .................................................................................... 39 
5.16 
Protocol Deviations .......................................................................................... 39 
5.17 
Dosing Errors ................................................................................................... 39 
5.18 
Study Completion: For Individual Subjects ..................................................... 39 
5.19 
Early Discontinuation ....................................................................................... 39 
5.20 
Subject Replacement ........................................................................................ 40 
5.21 
Study Completion: Overall .............................................................................. 40 
6 
STUDY PROCEDURES BY VISIT ......................................................................... 41 
6.1 
Scheduled Study Visits .................................................................................... 41 
6.1.1 
Screening (-30 days to Day 1) ........................................................... 41 
6.1.2 
Day 1 ................................................................................................. 41 
6.1.3 
Day 8 (+3 days) ................................................................................. 42 
6.1.4 
Day 15 (+3 days) ............................................................................... 42 

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6.1.5 
Day 29 (± 3 days) .............................................................................. 42 
6.1.6 
Months 3, 4, 5, 6 (90 to 180 days after Day 1 (± 5 days)) ................ 43 
6.2 
Early Discontinuation Visit .............................................................................. 43 
6.3 
Unscheduled Visits ........................................................................................... 44 
7 
SAFETY ...................................................................................................................... 45 
7.1 
Definitions ........................................................................................................ 45 
7.1.1 
Adverse Event ................................................................................... 45 
7.1.2 
Solicited Adverse Event .................................................................... 46 
7.1.3 
Unsolicited Adverse Event ................................................................ 46 
7.1.4 
Serious Adverse Event ...................................................................... 46 
7.2 
Severity Grading .............................................................................................. 47 
7.3 
Causality Assessment ....................................................................................... 47 
7.4 
Follow-up of Adverse Events ........................................................................... 48 
7.5 
Reporting of Adverse Events ........................................................................... 48 
7.5.1 
Reporting Periods .............................................................................. 48 
7.5.2 
Documentation .................................................................................. 49 
7.6 
SAE Reporting ................................................................................................. 49 
7.7 
Other Events Requiring Immediate Reporting ................................................. 51 
7.7.1 
Pregnancy .......................................................................................... 51 
7.8 
Medical Monitor ............................................................................................... 51 
7.9 
Data Monitoring Committee ............................................................................ 51 
7.10 
Study Stopping Rules ....................................................................................... 52 
8 
DATA HANDLING.................................................................................................... 54 
8.1 
Source Documentation ..................................................................................... 54 
8.2 
Retention of Study Documentation .................................................................. 54 
8.3 
Data Monitoring ............................................................................................... 54 
8.4 
Electronic Patient Reported Outcome Data ...................................................... 54 
8.5 
Laboratory Data ................................................................................................ 55 
8.6 
Audit Compliance ............................................................................................ 55 
9 
STATISTICAL ANALYSIS ...................................................................................... 56 
9.1 
Sample Size Calculation ................................................................................... 56 
9.2 
Treatment Period .............................................................................................. 56 
9.3 
Treatment Groups ............................................................................................. 57 

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9.4 
Populations for Analysis .................................................................................. 57 
9.5 
Demographic and Baseline Characteristics Analysis ....................................... 58 
9.6 
Safety Analysis ................................................................................................. 58 
9.6.1 
Analysis of Extent of Exposure ......................................................... 58 
9.6.2 
Solicited AEs ..................................................................................... 58 
9.6.3 
Unsolicited AEs ................................................................................ 59 
9.6.4 
Combined Solicited and Unsolicited AEs ......................................... 60 
9.6.5 
Analysis of Other Safety Data ........................................................... 60 
9.7 
Immunogenicity Analysis (50 to 64 years) ...................................................... 60 
9.7.1 
GMT/GMR ........................................................................................ 60 
9.7.2 
Threshold analyses ............................................................................ 61 
9.8 
Defined Safety Evaluation................................................................................ 61 
10 
ADDITIONAL INFORMATION ............................................................................. 62 
10.1 
Ethical Conduct of the Study ........................................................................... 62 
10.2 
IRB Oversight .................................................................................................. 62 
10.3 
Informed Consent ............................................................................................. 62 
10.4 
Subject Confidentiality ..................................................................................... 63 
10.5 
Compensation for Injury .................................................................................. 63 
10.6 
Clinicaltrials.gov .............................................................................................. 63 
10.7 
Public Disclosure and Publication Policy ........................................................ 63 
10.8 
Amendments..................................................................................................... 63 
11 
REFERENCES ........................................................................................................... 64 
 
 

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LIST OF TABLES 
 
 
 
 
 
Table 3 
Blood Collections .............................................................................................33 
Table 4 
Treatment Groups .............................................................................................57 
LIST OF FIGURES 
 
Figure 1 
Study Schema for Subjects 18 to 49 Years of Age ..........................................22 
Figure 2 
Study Schema for Subjects 50 to 64 Years of Age ..........................................23 
Figure 3 
Safety Events Reporting Periods ......................................................................49 

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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ACIP 
Advisory Committee on Immunization Practices 
AE 
Adverse Event 
ALPO 
Aluminum phosphate 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CRF 
Case report form 
CRO 
Contract research organization 
CRP 
C reactive protein 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
DP 
Drug Product 
eCRF 
Electronic Case Report Form 
eCRM 
Proprietary non-toxic diphtheria toxin carrier protein used in VAX-24 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
eSD 
Electronic Source Document 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GMC 
Geometric Mean Concentration 
GMFR 
Geometric Mean Fold Rise 
GMR 
Geometric Mean Ratio 
GMT 
Geometric Mean Titer 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C Virus 
HIV EIA 
Human Immunodeficiency Virus, Enzyme Immunoassay 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEP 
Immunogenicity Evaluable Population 

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Abbreviation 
Definition 
IgG 
Immunoglobulin G 
IM 
Intramuscular 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LLOQ 
Lower Limit of Quantitation 
MAAE 
Medically Attended Adverse Event 
MedDRA 
Medical Dictionary of Regulatory Activities 
MSD 
Meso Scale Discovery 
NOCI 
New Onset of Chronic Illness 
NZW 
New Zealand White (species of rabbits) 
OPA 
Opsonophagocytic assay 
pAMF 
Para-azidomethyl-L-phenylalanine 
 
 
PCV 
Pneumococcal Conjugate Vaccine 
PCV13 
Prevnar® 13 
PCV20 
Prevnar 20™ 
PD 
Pneumococcal Disease 
PFS 
Pre-filled Syringe 
PPV23 
Pneumovax® 23 
PS 
Polysaccharide 
S. pneumoniae 
Streptococcus pneumoniae 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMMP 
Safety Medical Management Plan 
SOC 
System organ class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
VAX-24 
24-valent investigational pneumococcal conjugate vaccine 
US 
United States 
WHO 
World Health Organization 

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PROTOCOL SYNOPSIS 
 
Sponsor 
Vaxcyte, Inc. 
Name of Investigational Product 
VAX-24 (24-valent Pneumococcal Conjugate Vaccine) 
Names of Comparator Products 
Prevnar 20™ (20-valent Pneumococcal Conjugate Vaccine; PCV20) 
Study Title 
A Phase 1/2a, Randomized, Observer-Blind, Dose-Finding, Controlled, Parallel-Group, Two-Stage Clinical 
Study to Evaluate the Safety, Tolerability, and Immunogenicity of a 24-Valent Pneumococcal Conjugate 
Vaccine (VAX-24) in Healthy Adults Aged 18 to 64 Years 
Study Number VAX24-101 
Study Phase 1/2a 
Study Sites 
Approximately 10 investigative sites in the US 
Study Objectives and Endpoints 
Primary: 
The primary objectives are: 
• 
To evaluate the safety and tolerability of a single injection of VAX-24 at three dose levels 
administered to healthy adults 18 to 64 years of age. 
• 
To compare the safety of VAX-24 to that of PCV20 administered to two control groups: 1) subjects 
18 to 49 years of age receiving PCV20, and 2) subjects 50 to 64 years of age receiving PCV20. 
Primary endpoints are: 
• 
Percentage of subjects reporting solicited local reactions within 7 days after vaccination (redness, 
swelling, and pain at injection site) in each age group. 
• 
Percentage of subjects reporting solicited systemic events within 7 days after vaccination (fever, 
headache, fatigue, muscle pain, and joint pain) in each age group. 
• 
Percentage of subjects reporting unsolicited AEs within 1 month after vaccination in each age 
group. 
• 
Percentage of subjects reporting Serious Adverse Event (SAE) and new onset of chronic illness 
(NOCI) within 6 months after vaccination. 
• 
Percentage of subjects reporting AEs with a new onset or a worsening of a condition that prompts 
the subject to seek unplanned medical advice at a physician's office, urgent care center, or 
Emergency Department (medically attended adverse event [MAAE]). 
Secondary: 
The secondary objectives are: 
• 
Safety: To assess laboratory value abnormalities and/or potentially clinically significant laboratory 
values following VAX-24 at 3 dose levels compared to control groups receiving PCV20 for subjects 
aged 50 to 64 years. 
• 
Immunogenicity: To assess the induction of antibody responses by VAX-24 dose levels compared to 
control groups receiving PCV20 for subjects aged 50 to 64 years. 
The secondary endpoints include the following: 
• 
Safety: Percentage of participants with laboratory value abnormalities and/or potentially clinically 
significant laboratory values at 1 month after vaccination. 

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PCV20 will be administered once, by IM injection, at a dose of 0.5 mL, as packaged by the manufacturer. 
Treatment and Duration of Treatment 
Treatment consists of a single IM injection of VAX-24 or a single IM injection of PCV20. 
Safety Assessments 
Subjects will be evaluated for solicited and unsolicited adverse events (AEs), including injection site 
reactions following vaccine administration. Additionally, changes in laboratory values (complete blood count 
[CBC] and differential, chemistry; tests for HIV EIA, HBsAg, HCV Ab, urinalysis), NOCI, physical 
examinations, and vital signs following administration of study vaccines will be evaluated. 
Statistical Methods 
Various standard statistical methods will be employed to analyze the data, including descriptive statistics, 
linear models, and graphical displays. 
Summary statistics will consist of frequencies and percentages of responses in each category for discrete 
measures and of counts, means, medians, standard deviations, 95% confidence intervals, and minimum and 
maximum values for continuous measures, and will be presented by study treatment. 
All calculated fields will be listed in various data listings for review. Additional analyses may be performed 
by the Sponsor to supplement these results. 
Version 9.4M6 (TS1M6) or higher of the SAS® statistical software package will be used to provide all 
statistical analyses. 

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1 
INTRODUCTION 
1.1 
Background and Rationale 
 
Streptococcus pneumoniae (S. pneumoniae) is the pathogen that causes pneumococcal disease 
(PD), classified as either non-invasive (otitis media, sinusitis, pneumonia) or invasive 
(bacteremia, meningitis). A persistent global incidence of PD, driven by emerging serotypes not 
covered by currently available vaccines, has resulted in high morbidity and mortality worldwide. 
Pneumococci cause over 50% of all cases of bacterial meningitis in the US (Gierke 2015). 
Mortality rates for invasive pneumococcal disease in the United States range from 11% to 30% 
in adults (Centers for Disease Control and Prevention 2018). The overall case-fatality rate for 
pneumococcal bacteremia is approximately 20% overall, increasing to 60% in the elderly 
(Centers for Disease Control and Prevention 2021). Pneumococcal pneumonia case fatality rates 
are also quite significant, estimated to be 5% to 7% overall with much higher rates also among 
elderly persons (Gierke 2015). In a prospective population-based cohort study of adult residents 
in Louisville, Kentucky, from 1 June 2014 to 31 May 2016, mortality during hospitalization was 
6.5%, corresponding to an estimated 102,821 annual deaths in the United States (Ramirez 2017). 
Despite substantial reductions in PD with the availability of pneumococcal conjugate vaccines 
(PCVs), due to the diversity of serotypes and the phenomenon of serotype replacement, a 
significant burden of PD remains which is currently not covered by Prevnar 13® (PCV13). In 
fact, just 28.6% of invasive PD cases in individuals ≥5 years old in the US in 2017 are due to 
serotypes included in PCV13, while non-PCV13 serotypes accounted for 71.4% 
(Varghese 2020). In the United States, a PCV vaccine covering all the serotypes in PCV13 and 
Pneumovax® 23 (PPV23) would increase serotype coverage from 28.6% in individuals (>5 years 
old) for PCV13 to 69.6% for VAX-24, respectively, as calculated from the data in Table 1 
(Varghese 2020). 
In August 2014, the Advisory Committee on Immunization Practices (ACIP) recommended use 
of PCV13 followed by PPV23 for adults aged ≥ 65 years of age to protect against pneumococcal 
disease in the US. At the time, the recommendation was warranted because PCV13-type disease 
among adults was assessed to be an important public problem. However, in the long-term, ACIP 
recognized that continued reductions in PCV13-type disease due to indirect effects from 
pediatric PCV13 use might limit the utility of this recommendation (Matanock 2019). 
 
With the recent FDA approval of Prevnar20™ (PCV20), a 20-valent pneumococcal conjugate 
vaccine, the ACIP reconvened in October 2021 to revise their recommendation to use PCV20 
without a subsequent dose of PPV23 or use Vaxneuvance™ (PCV15) followed by PPV23. 
 
Even with the approval of PCV20, due to the diversity of serotypes and the phenomenon of 
serotype replacement, a significant burden of PD remains which is currently not covered by 
PCV20. For example, currently PCV20 is estimated to cover just over half the serotypes causing 
invasive PD in those ≥65 years of age. The estimated incremental coverage a 24-valent 

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pneumococcal conjugate vaccine could contribute above PCV20 varies between 8 to 15% in 
adults (Gierke 2021). However, adding valency to existing PCVs using conventional 
technologies has proven difficult, for several reasons. First, data show that as more carrier 
protein/polysaccharide (PS) conjugates are added to existing PCVs, immune responses to the PSs 
often decrease due to the cumulative amount of carrier protein, which immunologically competes 
with the PS antigens (Dagan 2010), as most recently seen with PCV20 (Prevnar 20 Package 
Insert 2021). Second, conjugating additional PSs to a carrier protein molecule may mask existing 
T-cell epitopes that are critically important in eliciting an immune response. In the PCV13 
carrier protein CRM197, approximately 20% of the 39 lysine residues border relevant T-cell 
epitopes (Choe 1992; Diethelm-Okita 2000; Raju 1995). Since conventional conjugation 
chemistry heterogeneously conjugates PSs to lysine residues independent of their proximity to 
T-cell epitopes, a bound PS may block the presentation of a T-cell epitope to the immune system, 
thus preventing the induction of a T-cell response. Meanwhile, the B-cell epitopes of both the 
carrier protein and the antigen are presented to the immune system, increasing B-cell competition 
for any available T-cell help. The masking of these critical epitopes prevents the conversion to a 
T-cell dependent immune response and negates the benefit of the carrier protein. This 
competition for T-cell help diminishes the immune response to the PS antigen and is believed to 
result in the phenomenon known as carrier suppression (Dagan 2010). 
To address this issue, Vaxcyte is developing its PCV product, VAX-24, using a novel process 
that combines site-specific conjugation to the carrier protein and a highly efficient conjugation 
chemistry. Vaxcyte employs a cell-free protein synthesis platform to insert the non-native amino 
acid para-azidomethyl-L-phenylalanine (pAMF) into eCRM, a recombinant version of CRM197. 
These pAMF residues serve as PS conjugation sites, and are inserted in place of purposefully 
selected lysines, such that critical T-cell epitopes remain consistently exposed upon conjugation 
to maximize the T-cell-dependent immune response. 
 
This first-in-human trial VAX24-101 is a dose-finding Phase 1/2a that will examine the safety, 
tolerability, and immunogenicity of the VAX-24 Drug Product (DP) vaccine at three different 
strengths, and the results will be compared to those for the currently recommended regimen of 
PCV20. The study will be conducted in healthy adult populations: aged 18 to 49 years and 50 to 
64 years. The trial will be enrolled in two sequential stages: a Phase 1 cohort of 64 subjects aged 
18 to 49 years will be enrolled for safety evaluation prior to enrolling the Phase 2 cohort of 800 
subjects aged 50 to 64 years, giving a total of 864 subjects. Subsequent studies will include 
individuals 65 years and older where the disease burden is the greatest. 

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1.2 
Name and Description of Investigational Vaccine 
 
VAX-24 consists of capsular polysaccharide antigens of Streptococcus pneumoniae 
(S. pneumoniae) serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 
18C, 19A, 19F, 20B, 22F, 23F, and 33F, with each of the 24 polysaccharides (one from each 
serotype) individually conjugated in a site-specific manner to a novel and proprietary 
recombinant diphtheria carrier protein referred to as eCRM, and mixed with aluminum 
phosphate (ALPO). 
 
VAX-24 is described further in Section 4. 
 

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1.2.2 Rationale for Dosage and Route of Administration 
 
The dosages of VAX-24 are 1.1 mcg/dose (low), 2.2 mcg/dose (mid), or 2.2/4.4 mcg/dose 
(mixed), where potency of the formulated vaccine is determined by quantification of each of the 
saccharide antigens in the individual glycoconjugates. Based on the body of literature available 
on conjugated pneumococcal vaccines, the closest comparison to VAX-24 to establish a dose 
range was PCV20. Each ‘Mid’ dose is formulated to contain a similar quantity of Streptococcus 
pneumoniae polysaccharides as that of PCV20, the current standard of care. The ‘Mixed’ dose 
includes a similar quantity as the ‘Mid’ with the exception of inclusion of a higher amount for 
seven serotypes: two important epidemiologically relevant serotypes (3, 19A), and five shown to 
exhibit a dose-dependent response during the development of PCV13 (Varghese 2020, 
Jackson 2007). By utilizing site-specific conjugation to the CRM protein carrier thereby 
increasing the PS-to-eCRM ratio and enhancing overall T-cell epitope exposure, VAX-24 may 
be more potent than PCV13 and so a dose roughly half that of PCV13 has also been included in 
this study. 
These doses are below or approximately equivalent to those used in the nonclinical toxicology 
studies. 
 
 

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2 
OBJECTIVES AND ENDPOINTS 
2.1 
Primary 
 
The primary objectives are: 
 
• To evaluate the safety and tolerability of a single injection of VAX-24 at three dose 
levels administered to healthy adults 18 to 64 years of age. 
• To compare the safety of VAX-24 to that of PCV20 administered to two control groups: 
1) subjects 18 to 49 years of age; and 2) subjects 50 to 64 years of age. 
 
Safety and tolerability will be assessed by measuring the incidence of solicited local and 
systemic adverse events (AEs), unsolicited AEs, serious adverse events (SAEs), new onset of 
chronic illness (NOCI), and medically attended adverse events (MAAEs): 
• Percentage of subjects reporting solicited local reactions within 7 days after vaccination 
(redness, swelling, and pain at injection site) in each age group 
• Percentage of subjects reporting solicited systemic events within 7 days after vaccination 
(fever, headache, fatigue, muscle pain, and joint pain) in each age group 
• Percentage of subjects reporting unsolicited AEs within 1 month after vaccination in each 
age group 
• Percentage of subjects reporting SAEs and NOCI within 6 months after the vaccination 
• Percentage of subjects reporting AEs with a new onset or a worsening of a condition that 
prompts the subject to seek unplanned medical advice at a physician's office, urgent care 
center, or Emergency Department (MAAE). 
2.2 
Secondary 
 
The secondary objectives are: 
 
• Safety: To assess laboratory value abnormalities and/or potentially clinically significant 
laboratory values following VAX-24 at 3 dose levels compared to control groups 
receiving PCV20 for subjects aged 50 to 64 years. 
• Immunogenicity: To assess the induction of antibody responses by VAX-24 dose levels 
compared to control groups receiving PCV20 for subjects aged 50 to 64 years. 
 
The secondary endpoints include the following: 
 
• Safety: Percentage of participants with laboratory value abnormalities and/or potentially 
clinically significant laboratory values at 1 month after vaccination. 
• Immunogenicity: 24 VAX-24 Pneumococcal serotype-specific OPA geometric mean titer 
(GMTs) at 1 month after vaccination (Day 29). 

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3 
STUDY PLAN 
3.1 
Study Design 
 
This Phase 1/2a parallel-group, randomized, observer-blind study is to be conducted in two 
populations of healthy adults, 18 to 49 years of age and 50 to 64 years of age. Subjects will be 
randomly assigned in a 1:1:1:1 ratio to receive either VAX-24 at one of three dose levels 
(1.1 mcg, 2.2 mcg, or 2.2/4.4 mcg) or the comparator (PCV20). 
 
A Phase 1 cohort of 64 subjects (16 from each VAX-24 dose group and 16 from the comparator 
group) aged 18 to 49 years will be enrolled initially (Figure 1). Safety labs will be evaluated at 
screening for eligibility including pregnancy test for females of childbearing potential and safety 
labs will be repeated 28 days post-vaccination. Subjects will receive VAX-24 or PCV20 on 
Day 1. Solicited AEs will be collected for 7 days post-vaccination and unsolicited safety 
information for 28 days post-vaccination, with safety data (limited to SAEs, NOCIs, and 
MAAEs) collected up to 6 months post-vaccination. All the subjects in this age group will have 
blood samples drawn for safety labs at Screening and Day 29 (refer to Section 5.6). A defined 
safety review of data (AEs) through 7 days post-vaccination will occur by an independent data 
monitoring committee (DMC) before proceeding with enrollment of the Phase 2 subjects. 
Figure 1 Study Schema for Subjects 18 to 49 Years of Age 
 
 
 
 
A Phase 2 cohort of 800 subjects in the 50-to-64-year-old age range (200 in each arm) will be 
split into 4 groups (Figure 2). A minimum of 100 of the 800 subjects will be aged 60 to 64 years. 
Solicited AEs will be collected for 7 days post-vaccination and unsolicited safety information for 
28 days post-vaccination, with SAEs, NOCIs, and MAAEs collected up to 6 months post- 

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vaccination. All the subjects in this age group will have blood samples drawn for safety labs and 
immunogenicity analysis (OPA and IgG) at Screening and Day 29 (refer to Section 5.6). 
Figure 2 Study Schema for Subjects 50 to 64 Years of Age 
 
 
 
Approximately 100 subjects aged 50 to 64 years will be consented for additional blood 
collection, by a limited number of clinical sites. These subjects will have an additional 32 mL of 
blood collected per blood draw to be processed for peripheral blood mononuclear cells (PBMCs) 
to further characterize the immune response to VAX-24. Additional serum samples collected 
from all subjects aged 50 to 64 years may also be used for further characterization and validation 
of clinical assays. 
3.2 
Number of Study Participants 
 
The study population will be composed of at least 864 healthy US adults who meet the eligibility 
criteria listed in Section 3.4. 
 
Approximately 64 eligible subjects aged 18 to 49 and 800 subjects aged 50 to 64 years will be 
enrolled. 
3.3 
Estimated Study Duration 
 
The Screening period is 30 days, treatment and observation period is from Day 1 to Day 29, and 
the follow-up period is through Day 180 (6 months from study vaccination). The maximum 
possible study duration for an individual is 210 days. 

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3.4 
Study Population 
3.4.1 Inclusion Criteria 
 
Subjects must meet all of the following criteria in order to be enrolled: 
 
1. Male or female age 18 to 49 years (inclusive) for the Phase 1 group, or 50 to 64 years 
(inclusive) for the Phase 2 group at the time of enrollment into the study. 
2. Able and willing to complete the informed consent process. 
3. Available for clinical follow-up through the last study visit at 6 months after the study 
vaccination. 
4. In good general health as determined by medical history, vital signs, physical 
examination, and clinical judgment of the investigator. 
5. Screening laboratory values must be within the central laboratory normal limits1 prior to 
study enrollment. Minor abnormalities are considered acceptable if not clinically 
significant. 
Note: Laboratory values lower than the normal range may be acceptable if the Principal 
Investigator or a designated licensed clinician determines that these laboratory findings 
are not clinically significant. The HIV 1/2 antibody/antigen test, Hepatitis B surface 
antigen (HBsAg), and Hepatitis C virus (HCV) antibody must be non-reactive. 
6. Willing to have blood samples collected, stored indefinitely, and used for research 
purposes. 
7. Able to provide proof of identity to the satisfaction of the study staff completing the 
enrollment process. 
8. Negative pregnancy test (urine and serum) for women of childbearing potential. 
Non-pregnant, non-lactating females must also meet one of the following criteria: (a) no 
reproductive potential because of menopause (one year without menses) or because of a 
hysterectomy, bilateral oophorectomy, or tubal ligation; (b) subject agrees to be 
heterosexually inactive at least 14 days prior to vaccination and throughout the duration 
of the study; or (c) agrees to consistently practice contraception at least 7 days prior to 
enrollment and throughout the duration of the study by one of the following methods: 
condoms, male or female, with or without a spermicide, diaphragm or cervical cap with 
spermicide, intrauterine device, contraceptive pills or patch, Norplant, Depo-Provera, or 
other FDA approved contraceptive method, or a female with a male partner that has 
previously undergone a vasectomy. 
 
 
1 See Central Laboratory Manual for normal values. 

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3.4.2 Exclusion Criteria 
 
Subjects who meet any of the following criteria cannot be enrolled: 
 
1. Previous pneumococcal disease (either confirmed or by self-reporting). 
2. Previous receipt of a licensed or investigational pneumococcal vaccine. 
3. Receipt of any investigational study product within 30 days prior to enrollment into the 
study, currently participating in another interventional investigational study, or having 
plans to receive another investigational product(s) while on study. 
4. Planned or actual administration of any licensed vaccine during the period starting 
30 days before enrollment into the study through Day 29. 
5. Physical examination indicating any clinically significant medical condition. 
6. Body Temperature > 38.0°C (> 100.4°F) or acute illness within 3 days prior to study 
vaccination (subject may be rescheduled). 
7. Seropositive to HIV, HCV, or HBsAg. 
8. History of severe allergic reaction with generalized urticaria, angioedema, or 
anaphylaxis. 
9. Female who is breast-feeding or planning to become pregnant during study participation. 
10. Bleeding disorder diagnosed by a doctor (eg, factor deficiency, coagulopathy, or platelet 
disorder requiring special precautions) or significant bruising or bleeding difficulties with 
IM injections or blood draws. 
11. Any other chronic or clinically significant medical condition that, in the opinion of the 
investigator, would jeopardize the safety or rights of the subject or confound evaluation 
of the study vaccine, including but not limited to: diabetes mellitus type I, untreated 
hypertension, chronic hepatitis; or clinically significant forms of: drug or alcohol abuse, 
asthma, autoimmune disease, psychiatric disorders, heart disease, pulmonary disease, 
neurologic disease, cancer, or any known or suspected impairment immune function. 
12. Any medical, psychiatric, or social condition that, in the judgment of the investigator, is a 
contraindication to protocol participation or impairs a subject’s ability to give informed 
consent. 
13. Received blood or blood product (including Immune Globulin IV) within 90 days prior to 
enrollment into the study. 
14. Received systemic corticosteroids for ≥ 14 consecutive days and has not completed 
treatment ≤30 days prior to enrollment into the study. 

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15. Receiving immunosuppressive therapy, including chemotherapeutic agents used to treat 
cancer or other conditions, immunostimulants, and treatments associated with organ or 
bone marrow transplantation, or autoimmune disease. 
16. History of malignancy ≤5 years before enrollment, except for adequately treated basal 
cell or squamous cell skin cancer or in situ cervical cancer. 

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4 
STUDY VACCINE 
4.1 
Investigational Vaccine (VAX-24) 
 
VAX-24 is the Sponsor’s research name for a Pneumococcal Conjugate Vaccine. VAX-24 
consists of capsular polysaccharide antigens of Streptococcus pneumoniae (S. pneumoniae) 
serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 
20B, 22F, 23F, and 33F, with each of the 24 polysaccharides (one from each serotype) 
individually conjugated in a site-specific manner to a proprietary non-toxic diphtheria carrier 
protein referred to as eCRM, and mixed with ALPO. 
 
 
Each vial is filled to deliver a single 0.5 mL (extractable volume) dose of VAX-24 vaccine for 
IM administration, with no preservative.VAX-24 is manufactured by Laboratoire Baccinex 
(Switzerland) and will be supplied at three strengths in single-use 2 mL glass vials. The vial is 
sealed with a 13 mm gray bromo butyl rubber stopper with FluroTec® coating on the side in 
contact with VAX-24 DP. The stopper is capped with a 13 mm crimped aluminum seal with a 
flip-off white cap for Low strength, a blue cap for Mid strength, and a green cap for the Mixed 
strength. 
The three different strengths of VAX-24 will be identified as: 
 
• Low, 1.1 mcg of Total PS/dose per serotype 
• Mid, 2.2 mcg of Total PS/dose per serotype 
• Mixed, 2.2 or 4.4 mcg of Total PS/dose per serotype. Conjugate Drug Substance 
serotypes 3, 6B, 7F, 9V, 18C, 19A, and 19F are present at the higher level, with the other 
17 serotypes present at the lower level. 
 
The vaccine must be stored in a temperature-controlled refrigerator at 2°C to 8°C with 
controlled, limited access, and accessible to authorized personnel only. The temperature should 
be monitored by checking and recording current and maximum/minimum temperature readings 
inside the vaccine storage unit at least once each working day. 
4.1.1 Active Comparator 
 
Prevnar 20™ (PCV20), 20-valent pneumococcal conjugate vaccine is a sterile suspension of 
saccharides of the capsular antigens of S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 
10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F individually linked to non-toxic 
diphtheria CRM197 protein. PCV20 is manufactured by Wyeth Pharmaceuticals, LLC 
(subsidiary of Pfizer Inc.) and is commercially available in the US. Each 0.5 mL dose of the 
vaccine is formulated to contain approximately 2.2 mcg of each S. pneumoniae serotypes 1, 3, 4, 
5, 6A, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F, and 33F; 4.4 mcg of the 

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polysaccharide from serotype 6B; 51 mcg CRM197 carrier protein; and 100 mcg polysorbate 80, 
295 mcg succinate buffer, 4.4 mg sodium chloride, and 125 mcg aluminum as aluminum 
phosphate adjuvant. PCV20 pre-filled syringe (PFS) are to be stored at 2°C to 8°C (36°F to 
46°F), as required by the manufacturer. 
 
Refer to PCV20 Package Insert for clinical dosage and administration, storage and handling, 
contraindications, warnings and precautions, and summary of clinical trial results. 
4.1.2 Other Supplies 
 
The following supplies are provided by the Sponsor for preparation and administration of study 
vaccine: 
• 1 mL BD Luer-Lok™ Syringe sterile, single use polycarbonate 
• 25 Gauge BD™ Needle 1 inch single use, sterile 
• 25 Gauge BD™ Needle 1 1/2 inch single use, sterile 
4.2 
Dose Preparation of Study Vaccines 
 
A central supply depot will provide study vaccines and ancillary supplies. 
 
Unblinded site personnel will manage all aspects of the vaccine inventory; prepare the vaccine 
for administration; administer the vaccine and active comparator to study subjects; and store and 
monitor the vaccine in a secure area and maintain all accountability documentation. All study 
site personnel who complete subject assessments will be blinded to the vaccines being 
administered to study subjects. Unblinded site personnel will be trained in all aspects of vaccine 
management, preparation, and administration, and will be provided a Pharmacy Manual 
regarding such procedures. 
 
All study vaccines are parenteral drug products that should be inspected visually for particulate 
matter and discoloration prior to administration. The product should not be used if particulate 
matter or discoloration is found. VAX-24 and PCV20 are suspensions containing ALPO and 
should be shaken vigorously immediately prior to use to obtain a homogenous, white suspension 
in the vaccine container. The vaccines should not be used if they cannot be resuspended. 
 
All VAX-24 doses are to be withdrawn into Sponsor-provided syringes using sterile technique. 
No dilution or reconstitution is necessary. VAX-24 vial must be brought to room temperature 
and administered ≥ 10 minutes and ≤ 60 minutes. Once VAX-24 is withdrawn into a syringe, the 
dose must be administered within ≤ 60 minutes. Detailed instructions on packaging, preparation, 
administration, and accountability are found in the VAX24-101 Pharmacy Manual. 
 
PCV20 will be supplied to the clinical sites as single-use PFS packaged by the manufacturer. 
PCV20 should be administered by IM injection as soon as possible after being removed from 

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refrigeration. Preparation and administration instructions are found in the PCV20 Prescribing 
Information (manufacturer’s package insert) and should be adhered to. 
 
Each vaccine is administered IM in the deltoid muscle of the upper arm as a single dose of 
VAX-24 or PCV20. 
4.3 
Accountability Procedures for Study Vaccines 
 
It is the responsibility of the Investigator to supervise accurate monitoring of the receipt, storage, 
dispensing and accounting of all study material according to accepted industry practice. Sites 
must maintain and retain accurate, original site records of study material inventory as well as 
copies of all invoices of study material shipments and records of study material distribution. 
 
Drug accountability information will be collected in electronic source document format for 
tracking study vaccines (eg, date material was received, dispensed to individual subjects, and 
amount used and unused on site etc). 
 
Each site must keep all used and unused study material until the unblinded CRA has performed 
vaccine accountability and arranges return to the central repository vendor or gives instruction 
for used vaccine disposal. Expired vaccine should be separately quarantined until the unblinded 
CRA has completed accountability monitoring. 
 
Shipment of vaccine will be contingent on enrollment at the study sites. Detailed instructions on 
packaging, preparation, administration, and accountability are found in the VAX24-101 
Pharmacy Manual. 

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5 
STUDY PROCEDURES 
 
Source documents and source data will be captured electronically, meeting the same elements of 
data quality and integrity (ALCOA: attributable, legible, contemporaneous, original, and 
accurate) as paper records. Data will be collected into a fully validated system, with changes to 
data captured by automatic audit trail. The clinical trial site will use their own tablets or laptops 
to directly record subject data and clinical observations into electronic forms. Designated site 
staff will receive access to the system after appropriate training. As the trial uses electronic 
source documents as the original point of data capture, there is no additional data transcription 
step for the site to enter the CRF data into the application, except for the signed informed consent 
form (ICF). 
Some data may be captured via paper and subsequently transcribed into the eSource system. 
These source data will be verified by the clinical research associate and the location of the source 
data (ie, paper, local electronic system, etc) documented before the start of the trial. Copies of the 
paper source records will be uploaded into the eSource system for real-time access. 
 
Remote monitoring of original electronic source records will be performed, but on-site 
monitoring would occur for review of any paper source documents and their transcription into 
the system, etc. 
5.1 
Informed Consent 
 
The Investigator must obtain informed consent from study subjects at the Screening visit prior to 
starting any study-related activities. All prospective subjects must sign and date an Institutional 
Review Board (IRB)-approved ICF. For further details on informed consent, refer to 
Section 10.3. 
 
5.2 
Screening 
 
Screening procedures are listed in the Schedule of Events (APPENDIX A). 
 
Upon entry of a subject into the Screening Form within the electronic data capture (EDC) system, 
each Subject will be automatically assigned a unique Subject identifier. This Subject ID will be in 
the following format: 
 
Each subject who signs an ICF will receive a sequential three-digit identification number unique 
to the site (eg, 001, 002…). When screening information is subsequently entered into the EDC, 
each subject will be assigned a subject identification number with the following format: 
 
VAX24-101 ─ two-digit site number ─ three-digit identification number 
 
An example of a subject identification number is: VAX24-101 – 01 – 001. Subject numbers will 
also be sequential since screen-failed subjects will be entered into the EDC system. 

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Each site is required to record the reason(s) for screen failure for all subjects who receive a 
subject identification number within the EDC system. Sites may elect to use a pre-screening 
consent form, and maintain a pre-screening log for those subjects contacted for the study and will 
provide that log to the Sponsor or designee upon request. 
 
Re-screening 
 
A subject who meets exclusion criterion of having a current acute febrile illness at the time of 
scheduled enrollment may be re-screened after resolution of the acute illness. A subject who 
meets exclusion criteria of taking an investigational product, licensed vaccines, or medications 
(ie, systemic corticosteroid) within 30 days (or blood or blood product within 90 days) prior to 
Day 1 may be re-screened after the appropriate duration has passed. If an eligible subject is not 
able to be randomized and treated within 30 days of the Screening period, all screening 
procedures must be conducted again, including re-consenting and use of a new subject ID 
number. A subject may be re-screened one time only. Re-screening is not otherwise permitted. 
 
If a subject is re-screened, a new subject number will be assigned as they are entered into the 
EDC for a new Screening visit and the previous subject number will be captured in the source 
file of the newly assigned subject number. 
5.3 
Medical History 
 
Medical history information will be collected from subjects at the Screening Visit and confirmed 
at the Day 1 (Baseline) Visit. Medical history will include (but not be limited to) demographic 
information, current and past medical conditions, and prior and concomitant medications taken 
within 30 days prior to Day 1, including history of vaccinations. 
 
In consideration of the availability of commercial pneumococcal vaccines and ongoing 
investigational vaccine clinical research, the history of pneumococcal vaccination must be 
collected and, if the subject’s medical records and/or state-mandated vaccine registry are 
available, the site is required to maintain this documentation as part of the eligibility review. 
5.4 
Physical Examination 
 
A complete physical examination will be performed on subjects during the Screening visit. 
The examination should include: 
• Height 

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• Body weight 
• Vital signs 
• General appearance 
• Eyes-ears-nose-throat 
• Head-neck 
• Lungs-chest 
• Heart 
• Abdomen 
• Musculoskeletal 
• Lymph nodes 
• Skin 
• Extremities 
• Neurological 
 
A physical exam may be performed on subjects at additional time points if indicated by AE 
reporting. 
5.5 
Vital Signs 
 
Vital signs collected from subjects will include blood pressure, heart rate, respiratory rate, and 
oral temperature. The first set of Screening vitals are to be collected for inclusion of the subject 
into the study. Repeat measurements on abnormal vital parameters are allowed one additional 
time for inclusion into the study. After Day 1, abnormal vital signs can be repeated for 
confirmation of clinical significance. Vital signs should be taken after at least 5 minutes in 
supine position. 
5.6 
Laboratory Tests 
5.6.1 Blood Volume 
 
Blood is collected by venipuncture, in the appropriate blood container tubes according to the 
schedule of sample collection shown in APPENDIX A and Table 3. 
 
. The maximum volume of blood taken from a subject is up to ~54 mL, 
 
 
Phlebotomy will observe the American Red Cross limit of no more than 450 mL in any 8-week 
period. 

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Unscheduled laboratory tests may be performed if indicated by a change in medical condition 
(including clinically significant abnormal values). The volume to be collected will be appropriate 
to the tests performed. 
 
NOTE: ALL CRYOVIALS SHOULD BE FROZEN AND STORED AT -20o C OR 
COLDER AND SHIPPED ON DRY ICE. 
Table 3 
Blood Collections 
 
Study Day 
Blood 
volume 
(mL) 
Laboratory Tests 
Tube Type/volume 
Minimum # of 
2 mL cryovials 
Screening -30 to - 
1 
14 
Hematology 
Clinical Chemistry 
1 EDTA 2 mL 
1 SST 3.5 mL 
N/A 
Serology (HIV, HCV, 
HBsAg) 
Serum HCG (females 
only) 
1 SST 3.5 mL 
(+5 mL for 
confirmation) 
Run off SST tube 
Day 1 
17 (or 33)* 
Immunogenicity* 
2 SST 8.5 mL 
8 
 
 
 
Additional research 
Run off SST 
4 
Day 29 
5.5 
Hematology 
1 EDTA 2 mL 
N/A 
22.5 (or 
Clinical Chemistry 
1 SST 3.5 mL 
N/A 
38.5)* 
Immunogenicity* 
2 SST 8.5 mL 
8 
 
 
 
Additional research 
Run off SST tube 
4 
Total: ~20 mL for subjects aged 18 to 49 years; ~54 mL for subjects aged 50 to 64 
years; 
 
30 
Abbreviations: HBsAg = Hepatitis B surface antigen; HCG = human chorionic gonadotropin; HCV = Hepatitis C 
virus; HIV = human immunodeficiency virus; N/A = not applicable; 
 
 
* Immunogenicity and PBMC sample collection would only be collected from subjects aged 50 to 64 years old. 
 
Samples are obtained during the trial according to APPENDIX A. At each time point, blood is 
collected in the appropriate blood tube(s). 
 
Upon review and approval by the sponsor, the clinical sites will adhere to their standard 
operating procedures for collecting and storing PBMCs. Upon receipt at the central laboratory, 
these samples will be stored in liquid nitrogen. 
 
To minimize the impact of lost or damaged shipments, the frozen serum 
 samples will 
be sent in separate consignments (primary, backup) to the central laboratory. 

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Further details regarding specimen collection, processing, and shipping will be provided in the 
Central Laboratory Manual. 
5.6.2 Safety Laboratory Assessments 
 
Biological samples will be collected for the following clinical laboratory tests and shipped to the 
central laboratory for analysis: 
 
Hematology: Hemoglobin, White blood cell count (absolute), Neutrophils (absolute), 
Eosinophils (absolute), Platelet count 
 
Clinical Chemistry: Albumin, Alkaline phosphatase, Alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), Bilirubin (total and direct), Blood urea nitrogen, 
Calcium, Carbon dioxide, Chloride, Cholesterol and triglycerides, Creatinine, Glucose 
(random), Gamma-glutamyl transferase (GGT), Lactate dehydrogenase, Phosphate, 
Potassium, Sodium, Total serum protein, Uric acid 
 
Urinalysis: Specific gravity, pH, Glucose, Protein (Total), Ketones, Bilirubin, 
Urobilinogen, Hemoglobin, Leucocyte esterase, Nitrite 
 
Serology: HIV 1/2 antibody/antigen test, HBsAg, Hepatitis C virus antibody (HCV Ab) 
 
Pregnancy: Serum test at Screening visit only 
 
Urine pregnancy tests will be conducted at the site using a dipstick before vaccination. 
 
Screening safety lab results are required for subject eligibility in order to be enrolled in the study 
at Day 1. Screening safety labs will be used as baseline if a subject meets eligibility for 
enrollment into the study. Screening laboratory tests reported as minor abnormalities are 
considered acceptable if not clinically significant (eg, MCV). Repeating the screening tests once 
is permitted for out-of-range values, provided there is an alternative explanation for the 
out-of-range value. This alternative explanation should be documented in the subject’s source 
documents. 
 
Unscheduled laboratory tests will be performed if indicated by a change in medical condition 
(including clinically significant abnormal values). The volume to be collected will be appropriate 
to the tests performed. The toxicity grading scales for clinical laboratory values (FDA 2007) 
must be used when assigning severity to an out-of-range laboratory value; however, not all out of 
range laboratory values are considered AEs and need to be evaluated according to Section 7.1.1, 
Adverse Events. 
 
Further details regarding specimen collection, processing, and shipping will be provided in the 
Central Laboratory Manual. 

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5.6.3 Immune Response Assessments 
 
Serum antibody responses to pneumococcal polysaccharides induced by vaccination will be 
measured using 2 standard assays, OPA and multiplexed Meso Scale Discovery (MSD). 
 
The OPA assay has been developed and qualified by Nexelis, a GCP-compliant central 
laboratory, to analyze the 24 polysaccharide antigens contained in VAX-24. The OPA assay has 
been consistently used as the method for measuring the functional capacity of pneumococcal 
antibodies, as antibodies to pneumococcal PS protect the host by opsonizing pneumococci 
(marking pneumococci for destruction) for phagocytosis (Burton and Nahm 2006). 
 
The MSD assay has been developed and qualified by Nexelis to measure IgG responses against 
the 24 polysaccharide antigens contained in VAX-24. The MSD multiplex 
electrochemiluminescent assay is an immunoassay platform that allows simultaneous 
measurement of responses against multiple antigens and has been used to evaluate responses to 
various pneumococcal conjugate vaccines (Marchese 2009, Goldblatt 2011, Feyssaguet 2019, 
and Nolan 2020). 
 
The immune responses (as assessed by OPA and IgG assays) against the 20 polysaccharide 
antigens common to PCV20 and VAX-24 (1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 
18C, 19A, 19F, 22F, 23F and 33F) will be compared in the various treatment groups (VAX-24 at 
3 different dose levels, and the comparator vaccine), and the 4 incremental polysaccharide 
antigens contained in VAX-24 (2, 9N, 17F and 20B) will be evaluated separately. 
 
Immunogenicity samples will be collected for subjects aged 50 to 64 years only.
 
 
5.7 
Pregnancy Testing and Contraception 
 
Female subjects of childbearing potential will undergo a serum Human Chorionic Gonadotropin 
(HCG) pregnancy test at Screening and a urine pregnancy test prior to each injection. The subject 
must have a negative pregnancy test prior to study vaccine administration. The Investigator must 
report any pregnancies as described in Section 7.7.1. Female subjects of childbearing potential 
must also use an acceptable method of contraception from prior to Day 1 through Day 180 
(throughout the study). The Investigator must confirm that contraception methods were initiated 
prior to Day 1 (eg, hormonal contraception) to be considered fully effective. 
 
For reporting a pregnancy, refer to Section 7.7.1, Pregnancy. 

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5.8 
Randomization 
 
Subject eligibility will be confirmed and documented by the Investigator immediately prior to 
randomization of each subject. 
 
Unblinded study staff will indicate on a Randomization eCRF within the EDC system that they 
want to generate a randomization number for the subject. When they indicate yes, a 
randomization number and treatment assignment will be generated from the EDC randomization 
module. The randomization number is separate from, and does not replace, the subject 
identification number which is assigned at Screening. The Unblinded Pharmacist or designee 
will prepare the treatment assigned and dispense the appropriate treatment to the Unblinded 
Administrator for administration. 
 
Randomization will be 1:1:1:1 for the four treatment groups within each age group (18 to 49, 
50 to 64). Within the 50 to 64 year group, subjects will be further stratified into two groups: 
50 to 59 and 60 to 64 years. The total sample size expected within the 50 to 64 year age group is 
800 subjects; there will be a minimum number of 100 subjects in the 60 to 64 year age group 
(25 per treatment arm). See Section 9.3 for further details on the sample sizes within each age 
group. 
 
A subject will be considered enrolled once a randomization number has been assigned within the 
EDC system. The study will be conducted as an observer-blind study. Neither subjects, clinical 
site evaluators including the investigators, nor the Sponsor will know subjects’ individual 
treatment assignments until all subjects have completed their participation in the study and the 
database has been cleaned and locked. 
 
The following safeguards will be employed to reduce the risk of inadvertent unblinding: 
 
• Each clinical site is required to have a blinding plan that outlines its process on blinding 
the subject in situations such as administration of IM injection with different syringe 
types, transfer of study vaccine to the clinic room for administration, providing initial 
training and reminders to the subjects to not disclose their experiences with the injections 
except with unblinded study staff. 
• No Sponsor personnel other than the designated unblinded monitor(s) and third-party 
unblinded biostatistics and programming staff will have access to the randomization 
treatment assignments. 
• Should any subject or blinded staff member become inadvertently unblinded, the 
Investigator will promptly (within 24 hours of the Investigator’s awareness of the error) 
disclose the event to the Sponsor clinical study manager and medical monitor in a blinded 
fashion (disclosing only subject number, not treatment) so that corrective action can be 
initiated. The unblinding sequence of events will be documented as a protocol deviation 
and retained as source documents. See Section 5.15 for details on Emergency 
Unblinding. 

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5.9 
Study Vaccine Administration 
 
On Day 1 before study vaccine administration, the medical history, including physical exam (if 
indicated by updated medical history) and vital signs, and concomitant medications will be 
collected and updated in the subject file, serum 
 samples will be 
collected, and females of childbearing potential must have a negative urine pregnancy test. 
Immediately prior to study vaccine administration, staff should recheck subject eligibility. Once 
these procedures are performed, study vaccine will be administered. All doses of study vaccine 
are 0.5 mL in volume and are administered by IM injection with a Sponsor-provided 1 mL 
syringe and 25 gauge 1” (or 1.5”, at the Investigator’s discretion) needle as described above or 
PCV20 PFS, using universal precautions and sterile technique. All injections will be 
administered into the deltoid muscle. Injections will be administered by an unblinded staff 
member delegated by the Investigator. 
5.10 Acute Observation 
 
The subject will be monitored by blinded study staff for signs of an acute adverse reaction and 
vital signs will be obtained at least 30 minutes after injection. If a subject reports any symptom 
collected as Solicited AEs for this study, the blinded study staff will advise them to record the 
details in their electronic diary at the end of their day. 
 
Allergic reactions to the study vaccine are possible; therefore, appropriate drugs and medical 
equipment to treat acute anaphylactic reactions must be immediately available and a medically 
qualified study team member trained to recognize and treat anaphylaxis must be present in the 
clinic during the entire post-dosing monitoring period. 
5.11 Solicited Adverse Events 
 
Solicited AEs will be collected for 7 days after vaccine administration, starting on Day 1. 
Solicited AEs for this study are local events of pain, erythema (redness) and edema (swelling) at 
the injection site, and systemic events of oral temperature ≥ 100.4ºF, fatigue, headache, muscle 
pain, and joint pain. 
 
Subjects will be trained to complete a diary via IBM’s ePRO system. This system is accessed via 
a secure URL and will be used to observe, measure, and record these solicited AEs. A digital 
thermometer will be provided to the subject to measure oral temperature each day, and it is to be 
recorded daily in the diary. To record injection site local reaction, a ruler will be provided to the 
subject to measure the diameter of redness and swelling at the largest point of the reaction each 
day; it is to be recorded daily in the diary. 
 
Study staff will be provided with a Reference Guide for instructing subjects on accessing the 
IBM ePRO system. Each user will be provided with login credentials and a temporary password. 
The IBM ePRO system is web-based and accessed via a secure URL. 

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Study staff will review the signs and symptoms recorded in the diary and the action taken for the 
event during the subject’s clinic visit. The electronic diary will serve as the primary source 
document and data will be automatically integrated into the subject visit Solicited AE form in the 
EDC platform for site staff view-only access. The Investigator will then assess all recorded 
solicited events for severity and relatedness. Severity will be graded according to the FDA 
Toxicity Grading Scale (FDA 2007). The results of the Investigator’s assessment, if different 
from the subject’s entry, will be recorded in a separate field specified for Investigators within the 
EDC platform. For solicited injection site reactions, the relationship to study vaccine will be 
automatically recorded to be probably related, however, the Investigator will determine the 
relationship for each systemic solicited reaction. 
Symptoms continuing beyond the solicited AE collection period (7 days following each 
injection) will be collected and recorded as an unsolicited AE in the electronic source document 
(eSD). 
5.12 Unsolicited Adverse Events 
 
Unsolicited AEs (any AEs not listed in the diary) will be collected for this study. Details 
regarding definitions, evaluation, reporting periods, and documentation are outlined in Section 7. 
5.13 Prior and Concomitant Medications and Procedures 
 
At the Screening visit, the details of prior and concomitant medications and procedures (through 
30 days prior to Day 1) usage will be collected, including history of vaccinations. From Day 1 
through Day 29, the details of all concomitant medications and procedures including those 
associated with solicited AEs and unsolicited AEs will be collected. 
 
Concomitant medications and procedures associated with an SAE, NOCIs, and MAAE will be 
collected through the end of the study. 
5.14 Prohibited Medications and Therapies 
 
Subjects must not have received or be planning to receive: 
 
• Licensed or investigational pneumococcal (pneumonia) vaccine. 
• Investigational agents or study product from 30 days prior to Day 1 through the duration 
of the study. 
• Other (non-pneumococcal) licensed vaccines from 30 days prior to Day 1 through 
Day 29. 
• Blood or blood product (including IGIV) from 90 days prior to Day 1 through the 
duration of the study. 
• Systemic immunosuppressant therapy (eg, chemotherapeutics) and immunostimulants. 

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• Immunomodulatory medications (eg, oral corticosteroids) from 30 days prior to Day 1 or 
received systemic corticosteroids exceeding physiologic replacement doses within 
14 days prior to study vaccination through Day 29. 
 
The history of all prohibited medications at any time during study participation (regardless of 
association with an AE) will be collected. 
5.15 Emergency Unblinding 
 
The Investigator may obtain a treatment assignment for a study subject only in the case of a 
medical emergency in which knowledge of the treatment is necessary for the management of an 
AE. 
 
The Investigator must notify the Medical Monitor (and as backup, Medical Director) no later 
than 24 hours following Unblinding. Additional details for this unblinding process are provided 
in the Pharmacy Manual. 
5.16 Protocol Deviations 
 
The Investigator and delegated staff are responsible for conducting the study in accordance with 
the protocol. Any deviation from the protocol must be documented in the study file. In addition, 
deviations must be reported to the IRB as applicable. Subject-specific deviations must be 
recorded in the subject’s source documents. The Sponsor will review all protocol deviations on 
an ongoing basis and will be responsible for categorizing protocol deviations as exclusionary or 
not. 
5.17 Dosing Errors 
 
The Investigator or designee must report any error in the dosing of study vaccine to the 
site-assigned unblinded CRA and Medical Monitor or designee within 24 hours of the 
Investigator’s awareness of the error. Additional information regarding the dosing error may be 
provided as a follow-up report. A dosing error without signs or symptoms is not considered an 
AE but may be determined to be an important protocol deviation and investigated further. 
5.18 Study Completion: For Individual Subjects 
 
An individual subject is considered to complete study participation after completion of the 
Day 180 visit and completion of any required safety follow-up. 
5.19 Early Discontinuation 
 
An individual subject is considered to undergo Early Discontinuation if the subject stops study 
participation before the Day 180 visit. 

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An enrolled subject may voluntarily withdraw consent for further participation at any time before 
the Day 180 visit. The Investigator will request (but cannot require) such subjects to provide the 
reason(s) for withdrawal of consent and to undergo an Early Discontinuation visit. 
 
In addition, the Investigator, at his or her discretion, may withdraw a subject from further 
participation in the study. Criteria for withdrawal by the Investigator include: 
• Noncompliance with the protocol 
• Pregnancy 
• Immediate hypersensitivity reaction associated with a study injection 
• Loss to follow-up – requires documentation of at least 3 unsuccessful attempts to contact 
the subject. Lost to follow-up will be determined after the date of the subject’s projected 
last visit. 
• Other reason(s) which, in the opinion of the Investigator, indicates that continued 
participation in the study is not in the best interest of the subject. 
 
The Investigator or designee must report any early discontinuation for safety reasons to the 
Medical Monitor or designee within 24 hours of discontinuation. Additional information 
regarding ongoing AEs may be provided as a follow-up report. 
5.20 Subject Replacement 
 
Subjects who undergo Early Discontinuation after randomization and before Day 1 vaccine 
administration may be replaced by randomizing an additional subject at the Sponsor’s discretion. 
Subjects who undergo Early Discontinuation after study vaccination will not be replaced. 
5.21 Study Completion: Overall 
 
The study is planned to be completed after all subjects have completed the Day 180 (Month 6) 
visit (or Early Discontinuation, as appropriate), all necessary safety follow-up has been 
completed, and all data have been monitored and queries have been resolved. The Sponsor 
reserves the right to terminate the study prior to the planned study completion. 

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• Urine pregnancy test (females of childbearing potential) 
• Prior and concomitant medications 
• Randomization 
 
All eligible, consented, and randomized subjects will be vaccinated at the Day 1 Baseline visit. 
 
• Study vaccine administration, either VAX-24 or PCV20 
 
The following will take place during the visit and after study vaccine administration: 
 
• Acute observation for at least 30 minutes after vaccine administration 
• Vital signs collected at least 30 minutes after vaccine administration 
• AE (solicited and unsolicited) and SAE evaluation 
• Concomitant medications 
• Instructions on completion of an electronic diary, use of a ruler and thermometer 
6.1.3 Day 8 (+3 days) 
 
The following procedures will take place at this visit: 
 
• Visual inspection of injection site location 
• Review of diary data with the subject; Investigator’s assessment of severity and 
relationship to study vaccine 
• Concomitant medications 
• AE (solicited and unsolicited) and SAE evaluation 
6.1.4 Day 15 (+3 days) 
 
This visit is a follow-up phone call for safety evaluation. The following procedures will take 
place at this visit: 
• Concomitant medications 
• AE (unsolicited) and SAE evaluation 
6.1.5 Day 29 (± 3 days) 
 
The following procedures will take place during this visit: 
 
• Concomitant medications 
• AE (unsolicited) and SAE evaluation 
• Biological specimen collection for clinical laboratory tests: 

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7 
SAFETY 
7.1 
Definitions 
7.1.1 Adverse Event 
 
An adverse event is any untoward medical occurrence in a study subject, regardless of the 
suspected causal relationship with study vaccine. 
 
The definition of an AE includes: 
 
• A new-onset symptom or disease 
• An exacerbation of a pre-existing symptom or disease 
• A new-onset laboratory abnormality considered by the Investigator to be clinically 
significant 
• A new-onset symptom or disease that occurs as a result of a protocol-specified procedure 
The definition of an AE does not include: 
• A pre-existing symptom or disease that does not worsen during the study (even if first 
disclosed by the subject after the start of the study) 
• A medical or surgical intervention such as surgery, endoscopy, tooth extraction, or 
transfusion (although the condition leading to the procedure or a complication from the 
procedure may be an AE) 
• An uncomplicated pregnancy 
• A dosing error without any resulting signs or symptoms 
• Any other situation where an untoward medical occurrence has not occurred (eg, 
hospitalization for cosmetic elective surgery or social admissions) 
 
The definition of a treatment emergent AE (TEAE) is an event that occurs after vaccination and 
within the 28 days after vaccination (ie, excluding those after a subject has given informed 
consent, but before vaccination). 
 
The definition of a NOCI includes: 
 
A new-onset of chronic illness is a disease or condition, that is newly diagnosed, requires 
ongoing medical attention and/or limits activity of daily living, eg, heart disease, cancer, 
diabetes. 
 
The Investigator will attempt to establish a diagnosis based on signs, symptoms, and other 
clinical information. Whenever possible, the Investigator will report an AE as a diagnosis rather 
than one or more signs or symptoms. If a clinically significant laboratory abnormality meets the 

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definition of an AE, a diagnosis or clinical signs and symptoms rather than the abnormal 
laboratory finding should be reported if possible. If no diagnosis is known and clinical signs and 
symptoms are not present, but the laboratory abnormality is clinically significant by itself, then it 
should be reported as the AE. 
7.1.2 Solicited Adverse Event 
 
A solicited AE is a protocol-specified AE about which the Investigator or designee proactively 
asks the subject during a protocol-specified time period. Solicited AEs for this study are local 
events of pain, erythema (redness) and edema (swelling) at the injection site, and systemic events 
of fever (oral temperature ≥ 100.4ºF), fatigue, headache, muscle pain, and joint pain. 
7.1.3 Unsolicited Adverse Event 
 
An unsolicited AE is an AE that is spontaneously reported by the subject or discovered by the 
Investigator. New onset of chronic illness(s) would be recorded as part of the collection of 
unsolicited AEs as specified in the visit procedures. Unsolicited AEs will be collected separately 
from solicited AEs. 
7.1.4 Serious Adverse Event 
 
An SAE is an AE (either solicited or unsolicited) which meets any of the following criteria: 
 
• Results in death 
• Is life-threatening 
• Requires hospitalization or prolongs an existing hospitalization 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Is a congenital anomaly or birth defect 
• Important medical event that may jeopardize the patient or subject and/or may require 
medical or surgical intervention to prevent one of the above outcomes 
 
The Investigator will evaluate all AEs for seriousness using the above criteria. 
 
“Life-threatening” means that, in the opinion of the Investigator, the subject was at immediate 
risk of death from the event as it occurred. It does not mean that the event might have caused 
death had it occurred in a more severe form. 
 
Hospitalization for observation or for elective treatment of a pre-existing condition that did not 
worsen during the study is not considered an SAE. 
 
Important medical events may be considered serious at the discretion of the Investigator. 

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7.2 
Severity Grading 
 
The Investigator will grade all AEs for severity. AEs listed in the Guidance for Industry, 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, September 2007 will be graded according to the criteria in the table. AEs 
not listed in the Toxicity Grading Scale will be graded as follows: 
• Mild (Grade 1) – No interference with activity 
• Moderate (Grade 2) – Some interference with activity 
• Severe (Grade 3) – Significant; prevents daily activity 
• Potentially Life-Threatening (Grade 4) – ER visit or hospitalization 
7.3 
Causality Assessment 
 
The Investigator will assess all AEs, including solicited AEs, for causality (relationship to study 
vaccine), assigning one of these three categories: Not Related, Possibly Related, or Probably 
Related. 
 
An AE will be considered “Not Related” to study vaccine if any of the following conditions are 
met: 
• An unreasonable temporal relationship between administration of the study vaccine and 
the onset of the AE (eg, the event occurred either before, or too long after, administration 
of the study vaccine for it to be considered related); 
• A causal relationship between the study vaccine and the AE is biologically implausible 
(eg, injury as a passenger in an automobile accident); 
• A clear alternative causality for the AE is present (eg, typical adverse reaction to a 
concomitant medication). 
 
An AE will be considered “possibly related” if there is a reasonable possibility that the AE may 
have been caused by the study vaccine. 
• A single occurrence of an event that is uncommon and known to be strongly associated 
with vaccine exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome) 
• One or more occurrences of an event that is not commonly associated with vaccine 
exposure, but is otherwise uncommon in the population exposed to the vaccine (eg, 
tendon rupture) 
• An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of vaccine administration) that 

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indicates those events occur more frequently in the vaccine treatment group than in a 
concurrent or historical control group 
 
An AE will be considered “Probably related” if there is evidence that the AE was caused by the 
study vaccine. 
7.4 
Follow-up of Adverse Events 
 
The Investigator must follow all AEs until resolution, until the condition stabilizes or is no 
longer clinically significant, or until the subject is lost to follow-up. 
 
The Investigator is responsible for ensuring the conduct of any supplemental investigations 
considered necessary to evaluate the AE. These may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. 
 
In the event of a non-fatal SAE, subjects will be instructed to contact the Investigator (or 
designee) immediately. All subjects experiencing an SAE will be evaluated by the Investigator or 
designee as soon as is feasible following the report of the SAE by the subject. In the event of a 
fatal SAE, the Investigator must provide the Sponsor with any available post-mortem findings, 
including histopathology. 
 
Additionally, the Sponsor may request that the Investigator perform or arrange for the conduct of 
supplemental investigations for one or more AEs. 
7.5 
Reporting of Adverse Events 
7.5.1 Reporting Periods 
 
The four reporting periods for solicited AEs begin immediately after study vaccine 
administration and continue for 7 days after the injection. The reporting period for unsolicited 
AEs is immediately after study vaccine administration on Day 1, continuing through Day 29. 
AEs that correspond to solicited AE terms but occur outside of (or continue past) the solicited 
AE collection periods are also collected through the unsolicited AE reporting periods. The 
reporting period for SAEs begins at the time of informed consent and continues for the duration 
of study participation. 
 
A summary of the reporting periods is presented in Figure 3. 

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Figure 3 Safety Events Reporting Periods 
 
 
 
 
7.5.2 Documentation 
 
The Investigator or designee will document all AEs in the subject’s source documents and 
solicited AEs into the source document file within 24 hours of awareness. 
 
All AEs should include: 
 
• Event term 
• Start and stop date 
• Severity 
• Seriousness (Yes/No) and if Yes, which Seriousness criteria were met 
• Relationship to Study Vaccine 
• Action taken in response to the AE 
• Action taken with Study Vaccine 
7.6 
SAE Reporting 
 
The Investigator or designee must report all SAEs to Vaxcyte Clinical Safety Team within 
24 hours of becoming aware of the event, using the SAE Form. The Investigator or designee 
must also enter SAEs into the eSD. 
 
E-mail transmission of the SAE Report Form is the preferred method to transmit thisinformation 
to the Vaxcyte Clinical Safety Team. If initial notification is provided via telephone, this does 

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not replace the need for the investigator to complete and sign the SAE Report Form within the 
designated reporting time frames. 
 
Communication Methods to the Vaxcyte Clinical Safety Team: 
 
E-mail (primary): 
clinicalsafety@vaxcyte.com 
 
Telephone (emergency): 
1 (650) 275-4554 
 
The SAE Form should be completed as thoroughly as possible and be signed by the Investigator 
or designee before reporting to Vaxcyte. The SAE Form must include an assessment of causality 
and should include a preliminary diagnosis if possible. All SAEs assessed as not related must 
include an alternate causality. 
 
In order to avoid delays in initial reporting, additional information regarding the SAE may be 
provided as a follow-up report. The Investigator may also modify the diagnosis, seriousness, 
and/or causality assessment based on this information. 
 
Vaxcyte will notify the Investigator of SAEs that meet criteria for expedited reporting to 
regulatory authorities. The Investigator is responsible for notifying the applicable IRB of these 
events and adhering to any other applicable local reporting requirements. 
 
The Sponsor will report AEs to FDA in accordance with 21 CFR 312.32. Specifically, the 
Sponsor will report unexpected fatal or life-threatening suspected adverse reactions no later than 
7 days after initial receipt of the information, and serious and unexpected suspected adverse 
reactions (SUSARs) no later than 15 calendar days after determining that the information 
qualifies for expedited reporting. 
 
It is also the responsibility of Vaxcyte to make the determination of which SAEs are SUSARs, as 
defined in 21 CFR 312.32. 
• Suspected adverse reaction means any AE for which there is a reasonable possibility that 
the drug caused the AE. 
• Unexpected adverse reaction means an AE that is not listed in the Investigator’s 
Brochure or is not listed at the specificity or severity that has been observed. 
 
All SUSARs, as agreed upon by the IND Sponsor, will be reported to FDA. SUSARs will be 
provided to all participating Investigators. 

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7.7 
Other Events Requiring Immediate Reporting 
7.7.1 Pregnancy 
 
The Investigator or designee must report all pregnancies to the Vaxcyte Clinical Safety Team 
within 24 hours of becoming aware of the pregnancy, using the Pregnancy Report Form. All 
pregnancies will be followed to outcome. Additional information regarding the pregnancy may 
be provided as a follow-up report. 
 
An uncomplicated pregnancy is not considered an AE. Complications of pregnancy may qualify 
as AEs or SAEs and would therefore be documented and reported as specified above. 
7.8 
Medical Monitor 
 
The Medical Monitor will be the first point of contact regarding safety and eligibility questions 
for the study and will work closely with the Medical Director to assess subject eligibility, AEs 
and SAEs that trigger the stopping and halting rules, and all other safety related questions from 
the sites. 
The Sponsor Medical Director will provide oversight for the study, review blinded safety data, 
subject eligibility, and assess causality of SAEs on an ongoing basis. 
7.9 
Data Monitoring Committee 
 
The DMC will consist of two persons (independent Subject Matter Experts) and an unblinded 
statistician to compile the data and present to the members. The DMC will independently review 
the 7 days post-vaccination unblinded safety data for the subjects aged 18 to 49 years before 

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advancing the study into the older adult population. Stopping rules will be observed during the 
active study vaccine administration periods (see Section 7.10) and the DMC will conduct ad hoc 
reviews if the study is paused, triggered by one of the Stopping Rules, in order to identify any 
emerging safety concerns. 
 
The DMC will refer to the DMC Charter for procedures. 
 
7.10 Study Stopping Rules 
 
The rules governing the halting or stopping of the study vaccine administration at any time during 
the study are defined by age groups 18 to 49 and 50 to 64 years in the Phase 1 and Phase 2 
segments of the clinical study, respectively. During the vaccination period(s), if any of the 
stopping rules are triggered, no further administration of study vaccine(s) will occur until safety 
data are reviewed by the DMC in communication with the Medical Director and the Investigator 
at the site where the event occurred, as needed. Study dosing may be resumed if the DMC 
determines it is safe to proceed with no modifications or with modifications to the protocol plans. 
 
Phase 1: Subjects aged 18 to 49 years 
 
• One (1) SAE regardless of relationship 
• One (1) or more subjects with a Grade 4 (potentially life threatening) assessed as at least 
possibly related to investigational product 
• Three or more subjects with a Grade 3 (severe) AE assessed as at least possibly related to 
investigational product 
 
Phase 2: Subjects aged 50 to 64 years 
 
• One (1) SAE assessed as at least possibly related to investigational product 
• One (1) or more subjects with a Grade 4 (potentially life threatening) assessed as at least 
possibly related to investigational product 
• Two or more subjects with the same or similar Grade 3 (severe) AE, including laboratory 
abnormalities, assessed as at least possibly related to investigational product other than 
solicited events 
• Eight (8) or more subjects with the same or similar Grade 3 (severe) solicited AE 
 
The appropriate regulatory authority will be informed in writing when either of the following 
occurs: 
• Study dosing is stopped 
• DMC has decided to resume or discontinue study activities 

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Enrollment may be resumed following review of available safety data by the Sponsor. 
 
Vaxcyte clinical safety team will refer to the VAX24-102 Safety Medical Monitoring Plan for 
detailed procedures on stopping rule reporting and safety oversight for the study. 

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8 
DATA HANDLING 
8.1 
Source Documentation 
 
The Investigator must maintain source documentation of all study conduct data and observations 
relevant to the study. This source documentation includes, but is not limited to, ICFs, original 
medical records, progress notes from the Investigator and study staff, laboratory reports, diary 
for solicited AEs, and documentation of study vaccine accountability. 
 
This study will not employ eCRFs but rather have the data fields incorporated into eSD within a 
validated system that is 21 CFR Part 11 compliant. All clinical information requested in this 
protocol will be recorded on these eSD. The only planned paper source documents will be the 
signed consent form and copies of medical records, and these can be uploaded as copies into the 
EDC platform. The Investigator is responsible for the adequacy and accuracy of all data entered 
on the eSD. The Investigator is also responsible for signing all eSD, after which they will be 
locked by the Sponsor to prevent further data entry or modification. 
 
For further information on eSD, please refer to the eSD Completion Guidelines. Details on data 
handling will be described in the CRO Data Management Plan. 
8.2 
Retention of Study Documentation 
 
The Investigator will maintain all study documentation, including copies of ICFs, eSD, and 
documentation of study vaccine accountability, for either 2 years following FDA or other 
regulatory approval of VAX-24, or 2 years after clinical development of VAX-24 is 
discontinued, unless a longer period is required by applicable law or regulation. The Investigator 
will destroy study documentation only upon instruction by the Sponsor and must notify the 
Sponsor upon completion of such destruction. Subject identity information will be maintained 
for 15 years unless a longer period is required by applicable law or regulation. 
8.3 
Data Monitoring 
 
The Sponsor or designee will monitor completed eSD at regular intervals throughout the study to 
verify adherence to the protocol; completeness, accuracy, and consistency of the data; and 
adherence to local regulations on the conduct of clinical research. The Investigator must make 
hard copy source documentation accessible to the Sponsor or designee as needed to verify the 
information in the eSD. The Investigator agrees to cooperate with the Sponsor or designee to 
ensure that any problems detected in the course of data monitoring are resolved. 
8.4 
Electronic Patient Reported Outcome Data 
 
This study will employ electronic transfers of external diary data generated from subjects 
recording solicited AEs and actions taken for 7 days post-vaccination within a validated system 

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that is 21 CFR Part 11 compliant. The Investigator is responsible for the adequacy and accuracy 
of data associated with severity and relationship to study vaccine. 
8.5 
Laboratory Data 
 
This study will employ electronic transfers of external laboratory data generated from clinical 
specimens collected by the Investigator. The Investigator is responsible for the adequacy and 
accuracy of data associated with collection of these specimens, and for determining clinical 
significance for all out of range values. 
8.6 
Audit Compliance 
 
The Investigator must permit the Sponsor and/or designee, regulatory agencies, and/or the IRB 
direct access to facilities and study documentation for the purpose of auditing study conduct. 
Direct access includes examining, analyzing, verifying, and reproducing any records and reports 
that are needed for the evaluation of the study. 

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9 
STATISTICAL ANALYSIS 
 
This Phase 1/2a study is designed to achieve both safety and immunogenicity objectives. 
 
The primary objectives are to evaluate the safety of a single injection of VAX-24 at three dose 
levels, and to compare the safety of VAX-24 to that of PCV20 administered to two control 
groups: 1) subjects 18 to 49 years of age receiving PCV20; and 2) subjects 50 to 64 years of age 
receiving PCV20. 
 
The secondary immunogenicity objectives are to assess the induction of OPA and IgG antibody 
responses by VAX-24 at three dose levels compared to the 20 PCV20 serotypes (1, 3, 4, 5, 6A, 
6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F and 33F), as measured at 
28 days after the injection (Day 29) and 4 non-PCV20 serotypes (2, 9N, 17F, 20B), measured at 
28 days after the injection (Day 29) for subjects aged 50 to 64 years. 
 
Endpoints will be analyzed by age group (18 to 49, 50 to 59, 60 to 64, and 50 to 64 years of age). 
Safety will also be summarized for all subjects combined (18 to 64 years of age). 
 
A statistical analysis plan will be generated and approved prior to the data freeze and treatment 
group unblinding for the primary safety and secondary immunogenicity endpoints through Day 
29 visits. Individual treatment unblinding will occur after the data is cleaned through the last 
Month 6 visits and final database lock. A single completed Clinical Study Report (CSR) will 
summarize safety findings through Month 6 for all 864 subjects and immunogenicity for 800 
subjects 50 to 64 years of age. 
9.1 
Sample Size Calculation 
 
For subjects 18 to 49 years of age, sample size is not driven by statistical assumptions for formal 
hypothesis testing but was based on the safety objective for the study. With 16 subjects, events 
that occur at a frequency of 15% or more will be detected with at least 92% probability and 
events that occur at a frequency of 10% or more will be detected with 81% probability. 
Therefore 16 subjects in each treatment group are proposed as the basis for the number of 
subjects in whom to conduct the first safety assessment. 
 
For subjects 50 to 64 years of age, sample size is not based on statistical justification. A total of 
800 subjects should provide sufficient information to assess safety and immunogenicity in the 
50 to 59 and 60 to 64 age groups. The sample size will also be adequate to plan future studies. 
9.2 
Treatment Period 
 
The Treatment period begins at the time of study vaccine administration and extends through the 
Day 29 visit. The Follow-up period spans the time following the Day 29 visit through Day 180 (6 
months after study vaccine administration). 

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9.3 
Treatment Groups 
 
Subjects will be randomized into 8 treatment groups as displayed in Table 4. 
 
Table 4 
Treatment Groups 
 
Treatment 
Group 
Age Cohort 
N 
Treatment Administered 
(VAX-24, mcg Total PS/dose per serotype; 
PCV20) 
Day 1 
1 
18 to 49 
16 
VAX-24, 1.1 mcg 
2 
18 to 49 
16 
VAX-24, 2.2 mcg 
3 
18 to 49 
16 
VAX-24, 2.2/4.4 mcg 
4 
18 to 49 
16 
PCV20 
5 
50 to 64 
200 
VAX-24, 1.1 mcg 
6 
50 to 64 
200 
VAX-24, 2.2 mcg 
7 
50 to 64 
200 
VAX-24, 2.2/4.4 mcg 
8 
50 to 64 
200 
PCV20 
Total 
864 
 
9.4 
Populations for Analysis 
 
Randomized Population: All screened subjects who provide informed consent, provide 
demographic and other Baseline Screening measurements, are randomized, and are assigned a 
study subject ID (number). Each subject will be analyzed as randomized (ie, according to the 
vaccine regimen to which the subject was randomized). 
 
Exposed Population: All subjects who receive at least one study vaccination. 
 
Safety Population: All subjects in the Exposed Population who provide safety assessment data. 
This generally includes any subjects not lost to follow-up at Day 1, as they will be at risk for 
reporting an SAE. Each subject will be analyzed as treated (ie, according to the vaccine regimen 
a subject received, rather than the vaccine regimen to which the subject may have been 
randomized). 
 
Immunogenicity Evaluable Population: For this Phase 1/2 study, the immunogenicity 
population will be analyzed as treated (ie, according to the vaccine regimen a subject receives, 
which may be different from the vaccine regimen to which the subject is randomized in the case 
of treatment errors). The Phase 1 subjects aged 18 to 49 years are not included in this population. 

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The Immunogenicity Evaluable Population (IEP) includes all subjects in the Exposed Population 
who: 
• Have no major protocol deviation that would impact immunogenicity assessment or other 
reason to be excluded as defined prior to unblinding or analysis. 
• Have not received a prohibited medication or vaccine. 
• Provide evaluable serum sample results for baseline, the relevant post-vaccination time 
points, and within the required time frames: 
o Baseline: Day 1 or within 30 days before study vaccine administration 
o Day 29: Day 26 through Day 34, inclusive 
9.5 
Demographic and Baseline Characteristics Analysis 
 
The demographic and baseline characteristics will be summarized descriptively according to age 
group, treatment group, and overall. Age, height, weight, and body mass index at enrollment will 
be summarized by reporting the mean, standard deviation, median, minimum, and maximum. 
The frequencies and percentages of subjects by sex, race, and ethnicity will be presented. 
 
Demographic data will be tabulated for the Randomized, Immunogenicity Evaluable, and Safety 
Populations. 
9.6 
Safety Analysis 
 
All safety analyses will be based on the Safety Population. 
 
9.6.1 Analysis of Extent of Exposure 
 
The frequencies and percentages of subjects with vaccinations will be summarized by age group 
and treatment group for the Randomized Population. 
9.6.2 Solicited AEs 
 
With the exception of redness and swelling, all solicited AEs (local and systemic) will be 
summarized according to severity grading scales defined in Section 7.2, from “mild” to 
“potentially life-threatening.” 
 
Solicited AEs will be recorded daily until 7 days post-injection within an electronic diary. The 
analyses of solicited AEs (any event, after any injection, and after each injection) will be 
performed by maximum severity and by treatment group. In addition, solicited AEs ongoing 
after 7 days post-injection will also be recorded as unsolicited AEs. 

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Frequencies and percentages of subjects experiencing each solicited AE will be presented by 
maximum severity. Summary tables showing the occurrence of any local or systemic solicited 
AE overall and at each time point will also be presented. 
 
The severity of redness and swelling recorded as diameters (cm) will be summarized according 
to categories based on the largest diameter linear measurement when the local reaction is present: 
• Grade 0/absent: 0 - 2.4 cm 
• Grade 1/mild: > 2.5 - 5.0 cm. 
• Grade 2/moderate: > 5.1 - 10.0 cm. 
• Grade 3/severe: > 10.0 cm. 
 
The following summaries of subjects will be performed: 
 
• Solicited events by day post-injection, for each event and for any event. 
• Time of first onset of solicited AEs, after injection, for each event and any event. 
• Solicited AEs by maximum event severity, after injection, for each event and for any 
event. 
• Duration of solicited AEs, after injection, for each event and maximum duration of any 
event. 
• Solicited AEs, occurrence of at least one event by category (local, systemic), after 
injection. 
 
For each of the time points or time intervals presented in the summaries, only subjects with at 
least one observation (ie, any non-missing values but excluding “Not done/unknown”) for the 
solicited AEs will be summarized. 
9.6.3 Unsolicited AEs 
 
All the unsolicited AEs occurring during the study will be recorded, regardless of their 
assessment of relatedness by the Investigator. 
 
The original verbatim terms used by Investigators to identify AEs in the eSD will be mapped to 
preferred terms using the MedDRA dictionary. The unsolicited AEs will then be grouped by 
MedDRA preferred terms into frequency tables according to system organ class (SOC). All 
reported AEs, as well as AEs judged by the Investigator as at least possibly related to study 
vaccine, will be summarized by treatment group, according to SOC and preferred term within 
SOC. When an unsolicited AE occurs more than once for a subject, the maximum severity 
reported and strongest reported relationship to the treatment group will be counted. 

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Only TEAEs will be summarized as defined in Section 7.1.1. The selection of unsolicited AEs 
and their assignment to time intervals will be done by day of onset and not by days 
ongoing/persisting. 
 
Unsolicited AEs will be summarized by alphabetic SOC and preferred term as follows: 
 
• Any unsolicited TEAE 
• Possibly or probably related unsolicited TEAEs 
• SAEs 
• Possibly or probably related SAE 
• Unsolicited TEAE leading to withdrawal 
• Any AE leading to death 
 
Listings of all TEAEs will be provided by subject. 
 
9.6.4 Combined Solicited and Unsolicited AEs 
 
Solicited AEs continuing beyond 7 days after any injection will be coded by MedDRA and 
combined with the unsolicited AEs. An overall summary of subjects with all combined solicited 
and unsolicited AEs, by SOC and preferred term, will be provided as well. 
9.6.5 Analysis of Other Safety Data 
 
The frequencies and percentages of concomitant medications will be tabulated by age group, 
treatment group, and overall. Medications will be coded using the WHODRUG dictionary. 
9.7 
Immunogenicity Analysis (50 to 64 years) 
 
9.7.1 GMT/GMR 
 
Immunogenicity analyses will be performed by age group (50 to 59 and 60 to 64) and overall 
(50 to 64 years). Analyses will be performed for both OPA titers (log10) and IgG titers (mcg/mL). 
All immunogenicity analyses will be based on the IEP and Exposed Population. 
 
The GMTs and GMCs will be analyzed via linear models. The primary model is an analysis of 
variance (ANOVA), with logarithmically-transformed titers (log10) as the dependent variable and 
treatment group and study site as the fixed effects in the model. The results included in the main 
tables of this report will be based on this basic ANOVA model. As a secondary analysis, in order 
to remove the effect of baseline concentration on the GMTs, an analysis of covariance 
(ANCOVA) will also be performed. The ANCOVA includes treatment group and study site as 
the fixed effects and log10 baseline titer as the covariate in the model. The rationale for including 

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baseline values as a covariate is that prior data have shown vaccine response is correlated with 
baseline antibody levels. 
 
The least squares means and their 95% confidence intervals (CIs) calculated based on the 
ANOVA and ANCOVA will be back transformed and reported as the group GMT and GMC 
values (adjusted for the mean baseline in the case of the ANCOVA). GMRs will also be 
calculated from the ANCOVA and ANOVA models. 
 
Comparisons between relevant groups will be based on the estimated adjusted GMTs measured 
at Day 29 for 24 serotypes in VAX-24 (of those 20 in PCV20), and mean square error calculated 
from the basic ANOVA model using contrast statements. The analysis of GMFR relative to 
Day 1 will also be computed using similar models. 
 
The main comparison of interest will be the three VAX-24 dose levels group versus the PCV20 
(20 serotypes) group. However, the three VAX-24 dose groups will also be compared in a 
pairwise fashion on a serotype by serotype basis. No adjustment for multiplicity will be applied 
and missing data will not be imputed. 
9.7.2 Threshold analyses 
 
For the 4 non-PCV20 serotypes that are in VAX-24, the % of subjects with a ≥ 4-fold increase in 
OPA titer will be evaluated using a logistic regression model, with an indicator variable for 
achieving a ≥ 4-fold increase in OPA titer as the dependent variable, and treatment group and 
study site as fixed effects and log10 baseline titer as a covariate. The difference in proportions 
achieving a ≥ 4-fold increase in OPA titer in each of the three VAX-24 dose levels group versus 
the PCV20 and the corresponding 95% CIs will be calculated. If the lower bound of the 95% CI 
is > 0.1, the VAX-24 dose will be deemed statistically superior to PCV20. 
The percentage of subjects achieving specified thresholds (eg, GMFR ≥ 4 in serotype-specific 
OPA and IgG, achieving OPA titer of at least serotype-specific LLOQ of the assay), and 
associated Wilson (score) 95% CI, will be calculated for the Day 29 visit data for each treatment 
group. A reverse cumulative distribution curve will be provided. Differences between pair-wise 
treatment groups may be determined via Fisher’s exact tests. 
9.8 
Defined Safety Evaluation 
 
A defined safety evaluation will be conducted for the Phase 1 cohort of subjects aged 18 to 
49 years, based on the safety data collected through Day 8. The results will be reported to the 
DMC by treatment group preserving the double-blind status on the subject level, unless the DMC 
requests unblinded individual treatments. After the interim safety analysis and DMC concludes 
that no safety concerns exist, the study will resume enrollment of subjects aged 50 to 64 years. 

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10 ADDITIONAL INFORMATION 
10.1 Ethical Conduct of the Study 
 
The study will be performed in accordance with the protocol and consistent with ICH GCP 
Guidelines and applicable local regulatory requirements and laws. 
10.2 IRB Oversight 
 
The study (protocol, informed consent form, recruiting materials, and any documents seen by the 
subject) will be reviewed and approved by an IRB appropriate to each study site. Subjects will 
not be recruited, consented, screened, or enrolled until the IRB has approved the required 
documentation. In addition, the IRB will review amendments to the protocol before their 
implementation. 
 
The Investigator will retain all correspondence with the IRB in the trial master file and forward 
copies of all IRB approvals to the Sponsor. 
10.3 Informed Consent 
 
The Sponsor or designee will provide a master ICF template to each site for development of a 
site-specific ICF. At the Investigator’s discretion, the site may develop a separate ICF for pre- 
screening as described in Section 5.2. 
 
All site-specific ICFs must be approved by the Sponsor or designee and the IRB and must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements. The Sponsor 
or designee will advise the Site of required changes to the master ICF template during the course 
of the study. 
 
The Investigator will ensure that each potential study subject is fully informed about the nature 
and objectives of the study and possible risks associated with participation. Before informed 
consent is obtained, the Investigator, or a qualified person designated by the Investigator, will 
provide the potential study subject with ample time and opportunity to inquire about the details 
of the trial, and will answer all relevant questions to the potential study subject’s satisfaction. 
The potential study subject will then decide whether or not to participate in the trial. The 
Investigator, or a qualified person designated by the Investigator, will obtain written informed 
consent from each study subject before any study-specific activity is performed. 
 
The Investigator will retain the original and any amended signed and dated Informed Consent 
Form(s) at the study site and provide a copy to each study subject. 

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10.4 Subject Confidentiality 
 
The Investigator will ensure that each subject’s anonymity is maintained. In all documents 
submitted to the Sponsor and/or its designee, subjects can be identified by subject ID number and 
initials. Documents not intended for submission to the Sponsor and/or its designee (eg, signed 
ICFs) must be maintained by the Investigator securely and must be in compliance with all federal 
laws and regulations and ICH GCP Guidelines. 
10.5 Compensation for Injury 
 
The Sponsor will adhere to local regulations and guidelines regarding clinical trial compensation 
to subjects whose health is adversely affected by taking part in the study. The applicable policy 
for compensation for injury will be described in the master ICF template. 
10.6 Clinicaltrials.gov 
 
For purposes of reporting to clinicaltrials.gov, the Sponsor is the responsible party and will 
provide information regarding this study in accordance with applicable regulations. 
10.7 Public Disclosure and Publication Policy 
 
All publication rights are delineated in the Clinical Study Agreement with the Investigator(s). 
 
10.8 Amendments 
 
The protocol may be amended only by the Sponsor. 
 
The IRB must generally be informed of all amendments prior to implementation. In addition, the 
Investigator must obtain IRB approval for any amendments likely to affect the safety of study 
subjects prior to implementation. 
 
The Sponsor may implement an amendment prior to IRB notification or approval only in order to 
eliminate an apparent, immediate hazard to study subjects. In that event, the Sponsor will notify 
the IRB in writing within 7 calendar days after the implementation. 
 
Amendments, including descriptions and rationales, will be documented in this section of the 
protocol. 

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