A Phase 3, Randomized, Observer-Blind, Placebo- Controlled Cross-over Study to Evaluate the Efficacy, Safety, and Immunogenicity of S-268019 for the Prevention of COVID-19
Phase: PHASE3
Conditions: SARS-CoV-2
Sponsor: Shionogi

CLINICAL STUDY PROTOCOL 
TITLE PAGE 
Protocol Title: 
A Phase 3, Randomized, Observer-Blind, Placebo-
Controlled Cross-over Study to Evaluate the Efficacy, 
Safety, and Immunogenicity of S-268019 for the 
Prevention of COVID-19  
Protocol Number: 
2126U0232 
Amendment Number: 
3 
Compound: 
S-268019
Study Phase: 
3 
Short Title: 
A Phase 3 Study of S-268019 for the Prevention of 
COVID-19 
Sponsor Name: 
Shionogi & Co., Ltd. 
1-8, Doshomachi 3 chome, Chuo-ku, Osaka 541-0045,
Japan
Issue Date: 
8 Jul 2022 
Confidentiality Statement 
This document and the information contained herein or attached hereto (“Confidential 
Material”) are confidential and proprietary to Shionogi & Co., Ltd. This Confidential 
Material should only be viewed by those individuals or companies that have been given 
prior authorization to do so by Shionogi & Co., Ltd. (“Authorized Users”). This 
Confidential Material should not be made available in any form to any person or 
company, other than the Authorized Users and their respective employees or associates 
on a need-to-know basis, without the written consent from Shionogi & Co., Ltd. 
NCT # NCT05212948

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Sponsor Signatory: 
 
 
 
Refer to electronic signature page  
 
Refer to electronic signature page 
 
On behalf of 
  
Shionogi & Co., Ltd. 
 
Date 
 
 
 
 
Sponsor Contact Information: 
, Shionogi & Co., Ltd. 
8F, Nissay Yodoyabashi East Bldg., 3-13, Imabashi 3-chome,  
Chuo-ku, Osaka 541-0042, Japan 
TEL:
 
FAX:
 
 
Medical Monitor Contact Information: 
 
, Shionogi & Co., Ltd. 
8F, Nissay Yodoyabashi East Bldg., 3-13, Imabashi 3-chome, 
Chuo-ku, Osaka 541-0042, Japan 
TEL:
 
FAX:
 
 
 
 

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Clinical Study Protocol: 2126U0232 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................... 1 
1. 
PROTOCOL SUMMARY .......................................................................................... 7 
1.1 
Synopsis ............................................................................................................ 7 
1.2 
Schema ............................................................................................................ 11 
1.3 
Schedule of Activities (SoA) .......................................................................... 12 
2. 
INTRODUCTION .................................................................................................... 16 
2.1 
Study Rationale ............................................................................................... 16 
2.2 
Background ..................................................................................................... 16 
2.3 
Benefit/Risk Assessment ................................................................................ 17 
3. 
OBJECTIVES AND ENDPOINTS .......................................................................... 18 
4. 
STUDY DESIGN...................................................................................................... 20 
4.1 
Overall Design ................................................................................................ 20 
4.2 
Scientific Rationale for Study Design ............................................................. 21 
4.3 
Justification for Dose ...................................................................................... 22 
4.4 
End of Study Definition .................................................................................. 22 
5. 
STUDY POPULATION ........................................................................................... 23 
5.1 
Inclusion Criteria ............................................................................................ 23 
5.2 
Exclusion Criteria ........................................................................................... 24 
5.3 
Lifestyle Considerations ................................................................................. 25 
5.4 
Screen Failures ................................................................................................ 25 
6. 
STUDY INTERVENTION ....................................................................................... 25 
6.1 
Study Intervention(s) Administered ................................................................ 25 
6.2 
Preparation/Handling/Storage/Accountability of Study Intervention ............. 27 
6.2.1 
Dose Preparation and Dispensing ......................................................... 27 
6.2.2 
Administration ...................................................................................... 28 
6.2.3 
Criteria for Delay of Study Vaccination ............................................... 28 
6.3 
Measures to Minimize Bias: Randomization and Blinding ............................ 28 
6.3.1 
Randomization ...................................................................................... 28 
6.3.2 
Blinding ................................................................................................. 29 
6.4 
Study Intervention Compliance ...................................................................... 30 
6.5 
Prior Therapy/Concomitant Therapy .............................................................. 30 
6.6 
Dose Modification of Study Intervention ....................................................... 31 
6.7 
Intervention after the End of the Study ........................................................... 31 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL................................................................. 31 

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7.1 
Discontinuation or Suspension of Entire Study and Participant 
Discontinuation or Suspension ....................................................................... 32 
7.1.1 
Discontinuation or Suspension of the Entire Study .............................. 32 
7.1.2 
Discontinuation or Suspension of Individual Participants .................... 32 
7.2 
Participant Discontinuation/Withdrawal from the Study ................................ 34 
7.3 
Lost to Follow-up ............................................................................................ 35 
8. 
STUDY ASSESSMENTS AND PROCEDURES .................................................... 36 
8.1 
Assessment Tool ............................................................................................. 36 
8.1.1 
Electronic Clinical Outcome Assessment (e-Diary) ............................. 36 
8.2 
Efficacy Assessments ...................................................................................... 37 
8.2.1 
Definition of Symptomatic COVID-19 ................................................ 37 
8.2.2 
Severity of COVID-19 .......................................................................... 38 
8.2.3 
Surveillance for COVID-19-related Symptoms .................................... 38 
8.2.4 
SARS-CoV-2 RT-PCR Test ................................................................. 39 
8.2.5 
Procedures in the Event of Suspected COVID-19 ................................ 40 
8.2.6 
Definition of Asymptomatic COVID-19 .............................................. 40 
8.3 
Safety Assessments ......................................................................................... 40 
8.3.1 
Physical Examinations .......................................................................... 41 
8.3.2 
Vital Signs ............................................................................................. 41 
8.3.3 
Pregnancy Test ...................................................................................... 42 
8.4 
Adverse Events, Serious Adverse Events, Medically Attended Adverse 
Events and Adverse Events of Special Interest ............................................... 42 
8.4.1 
Time Period and Frequency for Collecting AE, SAE, MAAE and 
AESI Information .................................................................................. 42 
8.4.2 
Method of Detecting AEs and SAEs .................................................... 43 
8.4.3 
Follow-up of AEs and SAEs ................................................................. 43 
8.4.4 
Regulatory Reporting Requirements for SAEs ..................................... 43 
8.4.5 
Pregnancy .............................................................................................. 43 
8.4.6 
Reactogenicity ....................................................................................... 44 
8.4.7 
Medically Attended Adverse Events .................................................... 45 
8.4.8 
Adverse Events of Special Interest ....................................................... 45 
8.4.9 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs ................................................................... 45 
8.4.10 
Special Situations - Abuse, Misuse, Overdose, and Medication Error . 45 
8.5 
Treatment of Overdose ................................................................................... 46 
8.6 
Pharmacokinetics ............................................................................................ 46 
8.7 
Pharmacodynamics ......................................................................................... 46 
8.8 
Genetics (Virus Genome Sequencing) ............................................................ 46 

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8.9 
Biomarkers ...................................................................................................... 46 
8.10 
Immunogenicity Assessments ......................................................................... 47 
8.11 
Health Economics OR Medical Resource Utilization and Health 
Economics ....................................................................................................... 47 
9. 
STATISTICAL CONSIDERATIONS...................................................................... 48 
9.1 
Statistical Hypotheses ..................................................................................... 48 
9.2 
Sample Size Determination ............................................................................. 48 
9.3 
Populations for Analyses ................................................................................ 48 
9.4 
Statistical Analyses ......................................................................................... 49 
9.4.1 
General Considerations ......................................................................... 49 
9.4.2 
Disposition of Participants .................................................................... 49 
9.4.3 
Demographic and Baseline Characteristics .......................................... 50 
9.4.4 
Intervention Compliance ....................................................................... 50 
9.4.5 
Concomitant Medications and Therapies .............................................. 50 
9.4.6 
Efficacy Endpoint ................................................................................. 50 
9.4.7 
Analysis of Primary Endpoint ............................................................... 51 
9.4.8 
Analysis of Secondary Endpoint(s) ...................................................... 52 
9.4.9 
Analysis of Exploratory Endpoint(s) .................................................... 52 
9.4.10 
Safety Analyses ..................................................................................... 52 
9.5 
Interim Analyses ............................................................................................. 53 
9.6 
Independent Data Monitoring Committee (IDMC) ........................................ 54 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ................................................................................................ 54 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ......... 54 
10.1.1 
Regulatory and Ethical Considerations ................................................. 54 
10.1.2 
Financial Disclosure .............................................................................. 55 
10.1.3 
Informed Consent Process .................................................................... 55 
10.1.4 
Data Protection ...................................................................................... 55 
10.1.5 
Committees Structure ............................................................................ 56 
10.1.6 
Dissemination of Clinical Study Data ................................................... 56 
10.1.7 
Data Quality Assurance ........................................................................ 56 
10.1.8 
Source Documents ................................................................................ 57 
10.1.9 
Study and Site Start and Closure .......................................................... 58 
10.1.10 
Publication Policy ................................................................................. 58 
10.1.11 
Study Administrative Structure ............................................................. 60 
10.2 
Appendix 2: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ............................................................ 61 
10.2.1 
Definition of AE ................................................................................... 61 

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10.2.2 
Definition of SAE ................................................................................. 62 
10.2.3 
Recording and Follow-up of AE and/or SAE ....................................... 63 
10.2.4 
Reporting of SAEs ................................................................................ 64 
10.3 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information ..................................................................................................... 66 
10.4 
Appendix 4: Grading of Solicited Local and Systemic Adverse Events ........ 70 
10.5 
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments .. 72 
10.6 
Appendix 6: List of AESIs .............................................................................. 75 
10.7 
Appendix 7: Abbreviations and Acronyms ..................................................... 77 
10.8 
Appendix 8: Investigator’s Signature ............................................................. 80 
11. REFERENCES ......................................................................................................... 81 
 
 
LIST OF IN-TEXT TABLES 
Table 1-1 
Objectives, Estimands and Endpoints ........................................... 7 
Table 1-2 
Disposition of Vaccination Participants ...................................... 10 
Table 1-3 
Schedule of Activities for Participants without COVID-19 ....... 12 
Table 1-4 
Schedule of Activities for Participants with 
Suspected/Confirmed COVID-19 (COVID-19 Illness Visits).... 14 
Table 3-1 
Study Objectives, Estimands and Endpoints .............................. 18 
Table 4-1 
Group Allocation and Vaccination Schedule .............................. 20 
Table 6-1 
Study Intervention(s) .................................................................. 26 
Table 8-1 
COVID-19-related Symptoms .................................................... 37 
Table 8-2 
Solicited Local and Systemic Adverse Events ............................ 44 
Table 8-3 
Immunogenicity Assessments ..................................................... 47 
 
LIST OF IN-TEXT FIGURES 
Figure 1-1 
Study Schematic .......................................................................... 11 
Figure 7-1 
Phase 3-4 Liver Chemistry Stopping Criteria and Increased 
Monitoring Algorithm ................................................................. 33 
Figure 7-2 
Phase 3-4 Liver Chemistry Increased Monitoring Algorithm 
with Continued Study Intervention for Participants with ALT 
or AST  3 × ULN but < 8 × ULN ............................................. 34 
 

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1. PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A Phase 3, Randomized, Observer-Blind, Placebo-Controlled Cross-over 
Study to Evaluate the Efficacy, Safety, and Immunogenicity of S-268019 
for the Prevention of COVID-19 
Protocol Number: 2126U0232 
Compound Number: S-268019 
Short Title: A Phase 3 Study of S-268019 for the Prevention of COVID-19 
Rationale: This study will assess the efficacy, safety and immunogenicity of S-268019-b, 
a candidate prophylactic vaccine for the prevention of coronavirus disease 2019 (COVID-
19). This study is planned to use the dose at which immunogenicity and safety were 
confirmed in the ongoing Phase 1/2 double-blind study of S-268019-b (2026U0221). 
Objectives and Endpoints:  The study objectives and endpoints are shown in Table 1-1. 
 
Table 1-1 
Objectives, Estimands and Endpoints 
Objectives 
Estimands/Endpoints 
Primary 
● To assess the efficacy of a 2-dose regimen of 
S-268019-b for the prevention of COVID-19 
in the Initial Vaccination Period prior to 
crossover in participants without evidence of 
infection before vaccination as compared to 
placebo. 
Population: Modified Intent to Treat (mITT) 
Population 
Endpoint: The first occurrence of SARS-CoV-2 
reverse transcription polymerase chain reaction (RT-
PCR)-positive symptomatic COVID-19 in the Initial 
Vaccination Period (ie, prior to crossover), with onset 
at least 14 days following the second vaccination in 
participants seronegative and PCR-negative at 
baseline. 
Intercurrent events: For participants who withdraw 
from the study prior to having met the criteria for the 
primary efficacy endpoint, the absence of data 
following these participants’ withdrawal will be 
treated as missing; participants who withdrew before 
14 days post second vaccination or who were 
diagnosed with SARS-CoV-2 infection prior to 14 
days post second vaccination in the Initial 
Vaccination Period will be excluded from the primary 
endpoint analysis. 
Summary measure: Vaccine efficacy (VE), 
calculated as 1-relative risk. (Relative risk is the 
incidence of infection in the intervention group 
relative to the incidence of infection in the control 
group.) 

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Objectives 
Estimands/Endpoints 
Key Secondary 
● To assess the efficacy of S-268019-b for the 
prevention of symptomatic infection of 
COVID-19 as compared to placebo. 
● The first occurrence of SARS-CoV-2 RT-PCR-
positive severe COVID-19 in the Initial 
Vaccination Period with onset at least 14 days 
following the second vaccination in participants 
seronegative and PCR-negative at baseline.  
● The first occurrence of SARS-CoV-2 RT-PCR-
positive symptomatic COVID-19 in the Initial 
Vaccination Period in participants seronegative and 
PCR-negative at baseline. 
● The first occurrence of SARS-CoV-2 RT-PCR-
positive severe COVID-19 in the Initial 
Vaccination Period in participants seronegative and 
PCR-negative at baseline.  
Secondary 
● To assess the efficacy of S-268019-b for the 
prevention of symptomatic infection of 
COVID-19 as compared to placebo. 
● The first occurrence of SARS-CoV-2 RT-PCR-
positive symptomatic COVID-19 in the Initial 
Vaccination Period with onset at least 14 days 
following the second vaccination in participants 
regardless of serostatus or PCR status at baseline. 
● The first occurrence of SARS-CoV-2 RT-PCR-
positive severe COVID-19 in the Initial 
Vaccination Period with onset at least 14 days 
following the second vaccination in participants 
regardless of serostatus or PCR status at baseline.  
● The first occurrence of SARS-CoV-2 RT-PCR-
positive symptomatic COVID-19 in the Initial 
Vaccination Period in participants regardless of 
serostatus or PCR status at baseline. 
● The first occurrence of SARS-CoV-2 RT-PCR-
positive severe COVID-19 in the Initial 
Vaccination Period in participants regardless of 
serostatus or PCR status at baseline.  
● To assess the efficacy of a 2-dose regimen of 
S-268019-b for the prevention of 
asymptomatic infection of COVID-19 in 
participants without evidence of infection 
before vaccination. 
● The first occurrence of asymptomatic SARS-CoV-
2 infection in the Initial Vaccination Period 
beginning 14 days following the second 
vaccination in participants seronegative and PCR-
negative at baseline. Antibodies to SARS-CoV-2 
N-protein will be used to determine natural 
infection and to determine the incidence of 
asymptomatic infection acquired during study 
follow-up. 
● To assess the safety and reactogenicity of 
S-268019-b. 
● The incidence of AEs, treatment-related AEs, 
SAEs, AESIs, MAAEs, solicited local AEs, and 
solicited systemic AEs, and vital signs in the Initial 
Vaccination Period and the Crossover Vaccination 
Period. 
● To assess the immunogenicity of a 2-dose 
regimen of S-268019-b in the subset of 
immunogenicity subset. 
● The following items for SARS-CoV-2 neutralizing 
antibody titer and anti-SARS-CoV-2 S-protein 

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Objectives 
Estimands/Endpoints 
immunoglobulin G (IgG) antibody titers from 
Immunogenicity subset: 
– Geometric mean titer (GMT) 
– Geometric mean of fold rise of antibody titer 
(GMFR) 
– Seroconversion rate 
Exploratory 
● To assess the durability of VE in the 
Crossover Vaccination Period. 
● The first occurrence of SARS-CoV-2 RT-PCR-
positive symptomatic COVID-19 in the Crossover 
Vaccination Period. 
● The first occurrence of asymptomatic SARS-CoV-
2 infection in the Crossover Vaccination Period. 
Antibodies to SARS-CoV-2 N-protein will be used 
to determine natural infection and to determine the 
incidence of asymptomatic infection acquired 
during study follow-up. 
● To explore SARS-CoV-2 genetic variants in 
participants diagnosed with COVID-19. 
● Nucleotide sequences of SARS-CoV-2 viral 
genomes detected in nasopharyngeal swabs from 
RT-PCR-positive participants analyzed with next-
generation sequencing.  
 
Overall Design:  
This study is a multicenter, randomized, observer-blind, placebo-controlled, cross-over 
phase 3 study to evaluate the efficacy, safety and immunogenicity of S-268019-b in 
participants ≥ 18 years of age. Eligible participants will be randomly assigned to either 
the S-268019-b-preceding-vaccination group or the placebo-preceding-vaccination group 
in a 2:1 ratio. The randomization will be stratified by age group (18 to 64 years and ≥ 65 
years). Participants will receive either S-268019-b or placebo on Day 1 and Day 29. 
Following approximately six-month follow-up from the second vaccination given during 
the Initial Vaccination Period, participants will be scheduled for administration of 2 
injections of the alternate intervention (blinded crossover, Day 225 and Day 253) in the 
Crossover Vaccination Period. A schematic overview of the study is presented in Figure 
1-1. 
Number of Participants: 
54,915 participants (36,610 participants in the S-268019-b-preceding group, 18,305 
participants in the placebo-preceding group). 
Intervention Groups and Duration: 
The study will be composed of a Screening Period (Day −28 to Day 1), an Initial 
Vaccination Period (Day 1 to Day 224), and a Crossover Vaccination Period (Day 225 to 
Day 435).  
In the Initial Vaccination Period, the efficacy of a 2-dose regimen of S-268019-b against 
COVID-19 will be assessed compared to placebo. Participants will be randomly assigned 

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to the S-268019-b-preceding group or the placebo-preceding group in a 2:1 
randomization ratio. Participants assigned to the S-268019-b-preceding group will 
receive S-268019-b and participants assigned to the placebo-preceding group will receive 
placebo. In the Crossover Vaccination Period, participants in the S-268019-b-preceding 
group will receive placebo and participants in the placebo-preceding group will receive 
S-268019-b. All participants who remain in the study at the time of the blinded crossover 
will be eligible for crossover vaccination, except for participants who have experienced 
an RT-PCR-positive COVID-19. The dose of the study intervention is shown in Table 
1-2. 
Participants will visit the study site on Days 1, 29, 57, 97, 225, 253 and 435, and receive 
a single-dose of study intervention by intramuscular injection on Day 1 and Day 29 in the 
Initial Vaccination Period, and on Day 225 and Day 253 in the Crossover Vaccination 
Period (Table 1-3). 
If a participant reports any COVID-19-related symptoms (Table 8-1), the investigator 
will instruct the participant to visit the study site as Potential COVID-19 Illness Visits 
(Table 1-4). Participants diagnosed with SARS-CoV-2 infection based on the RT-PCR 
test result will be monitored by the study investigator or subinvestigator for 28 days. If 
necessary, the investigator or subinvestigator instruct a participant to visit the study site 
(COVID-19 Illness Visit) and undergo appropriate examinations. The participant will 
visit the study site 28 days after Potential COVID-19 Illness Visit for follow-up (COVID-
19 Follow-up Visit). For participants who are diagnosed with COVID-19 before 
receiving the final vaccination, the subsequent vaccination will be cancelled, although 
they will continue to be assessed for the safety. While the diagnosis of COVID-19 will 
not be reported as an adverse event (AE), they will be reported as a serious adverse event 
(SAE) if they fulfill the definition of SAE. 
 
Table 1-2 
Disposition of Vaccination Participants 
Group 
Sample 
size 
Intervention in the Initial 
Vaccination Period 
Intervention in the Crossover 
Vaccination Period 
Day 1 
Day 29 
Day 225 
Day 253 
S-268019-b-preceding 
group  
36,610 
S-268019-b 0.5 mL 
Placebo 0.5 mL 
Placebo-preceding 
group 
18,305 
Placebo 0.5 mL 
S-268019-b 0.5 mL 
 
Independent Data Monitoring Committee: Yes 
 
 

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1.2 
Schema 
Figure 1-1 
Study Schematic 
Screening Period 
Initial Vaccination Period 
Crossover Vaccination Period 
Day -28 to Day 1 
(Screening Visit) 
Day 1 to Day 224 
(Visit 1 to Visit 4) 
Day 225 to Day 435 
(Visit 5 to Visit 7) 
 
 
 
S-268019-b-preceding 
group 
 
S-268019-b 
Vaccination 
Placebo  
Vaccination 
 
 
 
 
                       
                    
 
Randomization 
Vaccination 
(Day 1) 
Vaccination 
(Day 29) 
 
Vaccination 
(Day 225) 
Vaccination 
(Day 253) 
 
 
 
 
                       
                    
Placebo-preceding 
group 
 
Placebo 
Vaccination 
S-268019-b  
Vaccination 
 
 
 
If a participant has any of COVID-19-related symptoms (Table 8-1) during the study, he/she will visit the 
study site for the Potential COVID-19 Illness Visit. 

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1.3 
Schedule of Activities (SoA) 
Table 1-3 
Schedule of Activities for Participants without COVID-19 
Period 
Screening 
Period 
Initial Vaccination Period 
(Day 1 to Day 224) 
Crossover Vaccination Period 
(Day 225 to Day 435) 
Unscheduled 
Visit 
Screening a 
1 
2 
3 
4 
5 
6 
7 
 
Discontinuation 
Day 
-28 to 1 
1 
29 
(Visit 1+28) 
57 
(Visit 2+28) 
97 
(Visit 2+68) 
225 
(Visit 2 
+196) 
253 
(Visit 5+28) 
435b 
(Visit 6 
+182) 
Visit window (days) 
 
0 
±3 
±7 
±14 
±14 
±3 
±14 
+3c 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
Enrollment/Randomization 
X 
X 
 
 
 
 
 
 
 
Study intervention 
 
X 
Xd 
 
 
Xd 
Xd 
 
 
Physical examinatione 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
Demographicsg 
X 
 
 
 
 
 
 
 
 
Height, weight, BMI 
X 
 
 
 
 
 
 
 
 
Past and current medical conditions 
X 
 
 
 
 
 
 
 
 
Vital signs 
X 
Xf 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testh 
X 
← (X) → 
 
← (X) → 
 
X 
Nasopharyngeal 
swab sample 
SARS-CoV-2  
RT-PCR 
 
Xi 
 
 
 
 
 
 
 
Blood sampling 
for 
immunogenicity 
tests 
Anti-SARS-CoV-2 
N-protein antibodies 
 
Xi 
 
X 
X 
Xi 
Xi 
X 
X 
Anti-SARS-CoV-2 
S-protein IgG 
antibodiesj 
 
Xi 
Xi 
X 
X 
Xi 
 
X 
X 
SARS-CoV-2 NAbj 
 
Xi 
Xi 
X 
X 
Xi 
 
X 
X 
e-Diary 
COVID-19-related symptomsk 
 
←X→ 
X 
Solicited AE (reported by 
participants)l 
 
←Xl→ 
 
 
 
 
 
AE reviewm 
X 
←X→ 
 
←X→ 
 
X 

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Period 
Screening 
Period 
Initial Vaccination Period 
(Day 1 to Day 224) 
Crossover Vaccination Period 
(Day 225 to Day 435) 
Unscheduled 
Visit 
Screening a 
1 
2 
3 
4 
5 
6 
7 
 
Discontinuation 
Day 
-28 to 1 
1 
29 
(Visit 1+28) 
57 
(Visit 2+28) 
97 
(Visit 2+68) 
225 
(Visit 2 
+196) 
253 
(Visit 5+28) 
435b 
(Visit 6 
+182) 
Visit window (days) 
 
0 
±3 
±7 
±14 
±14 
±3 
±14 
+3c 
SAE, MAAE, AESI review 
X 
←X→ 
X 
Prior/Concomitant medication 
X 
←Xn→ 
X 
AE = adverse event; AESI = adverse events of special interest; BMI = body mass index; COVID-19 = coronavirus disease 2019; IgG = immunoglobulin G; MAAE = Medically 
Attended Adverse Event; N-protein = nucleocapsid protein; NAb = neutralizing antibody; RT-PCR = reverse transcription polymerase chain reaction; S-protein = SARS-CoV-2 
spike glycoprotein; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; W = week; M = month, V = visit; Vax = visit for vaccination 
a) 
Can be conducted on the same day as Day 1. 
b) 
6 months after 4th Vax. 
c) 
Within 3 days from decision to discontinue the study. 
d) 
Vaccination should be done within the visit window whenever possible, but it may be postponed for the reasons described in Section 6.2.3. 
e) 
A complete physical examination will be performed at screening followed by brief physical examinations. 
f) 
Assessed before vaccination. Need not to repeat in participants who are screened on Day 1. 
g) 
Including year of birth, age at the time of signing the informed consent form, sex, ethnicity, race, smoking status, medical history. 
h) 
Only for women of childbearing potential (WOCBP). The pregnancy test (urine or serum as required by local regulations) will be performed at screening and also when it is 
deemed necessary by the investigator or subinvestigator in the first 57 days of each period.  
i) 
Nasopharyngeal swab and blood samples will be collected before vaccination. 
j) 
Blood samples for anti-SARS-CoV-2 S-protein IgG antibodies and SARS-CoV-2 neutralizing antibodies will be collected from at least 650 participants (Section 8.10). 
k) 
Participants will complete surveillance for COVID-19-related symptoms at least once a week or whenever participants experience any new or worsened COVID-19-related 
symptoms.  
l) 
Solicited local and systemic AEs and body temperatures are recorded during the 7-day periods after the vaccinations (Day 1 to 8 and Day 29 to 36). 
m) 
AEs will be collected from the date of signing of the ICF to 4 weeks after the second vaccination (Initial Vaccination Period), and from the third vaccination to 4 weeks after 
the fourth vaccination (Crossover Vaccination Period). 
n) 
During Day 58 to 224 and Day 254 to 435, only concomitant medication for treatment of SAE, MAAE, or AESI, or prohibited medication will be collected. 
 
 

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Table 1-4 
Schedule of Activities for Participants with Suspected/Confirmed COVID-19 (COVID-19 Illness 
Visits) 
Visit 
Potential COVID-19 Illness Visit 
(COVID-19 Illness Visit)* 
COVID-19 Follow-up Visitg 
Days 
1a 
Unscheduled 
29 ± 3b 
Physical examination 
X 
(X) 
X 
COVID-19 assessment 
 
 
Xc 
Vital signs, SpO2 
X 
(X) 
X 
Chest X-ray/CT or blood gas analysisd 
← (X) → 
Pregnancy teste 
← (X) → 
Nasopharyngeal 
swab sample 
SARS-CoV-2 RT-PCR 
X 
 
 
Virus genome sequencing 
X 
 
 
Blood collection 
for the 
immunogenicity 
tests 
Anti-SARS-CoV-2 N-protein 
antibodies 
X 
 
 
Anti-SARS-CoV-2 S-protein 
IgG antibodies 
X 
 
X 
SARS-CoV-2 NAb 
X 
 
X 
e-Diary 
COVID-19-related symptomsf 
←X→ 
AE review 
←X→ 
SAE, MAAE, AESI review 
←X→ 
Concomitant medication 
←X→ 
AE = adverse event; AESI = adverse events of special interest; COVID-19 = coronavirus disease 2019; CT = computed tomography; IgG = immunoglobulin G; MAAE = 
Medically Attended Adverse Event, N-protein = nucleocapsid protein; NAb = neutralizing antibody; RT-PCR = real-time polymerase chain reaction; S-protein = SARS-CoV-2 
spike glycoprotein; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SpO2 = peripheral capillary oxygen saturation 
a) 
Within 3 days from the date when the investigator or designee instructs a participant to visit the site. The Potential COVID-19 Illness Visit may be conducted as an in-person 
visit or telehealth visit. In the case of telehealth visit, a qualified site staff will visit participant’s home or place of sojourn. 
b) 
The COVID-19 Follow-up Visit will occur only for participants with a positive RT-PCR result. 
c) 
Evaluate and record the severity of COVID-19, all the presented COVID-19 symptoms (including symptom onset date if there are any symptoms), and the presence or 
absence of RT-PCR tests outside the clinical trial sites (test results if performed). 
d) 
To be performed for participants with respiratory symptoms at the discretion of the investigator. 
e) 
Only for women of childbearing potential (WOCBP). The pregnancy test (urine or serum as required by local regulations) will be performed 
when it is deemed necessary by the investigator or subinvestigator. 
f) 
Participants will evaluate COVID-19-related symptoms daily until all symptoms have disappeared.  
g) 
If any COVID-19-related symptoms persist at the time of the COVID-19 Follow-up Visit, the investigator should continue the follow-up until the participant has fully 
recovered or been medically stable. 

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* 
COVID-19 Illness Visit(s) will be scheduled when the investigator judges participant’s visit and additional examinations such as physical examination, vital signs, SpO2, blood 
gas analysis, or chest X-ray/CT are necessary to manage COVID-19. If such examinations are performed, the results will be recorded in eCRF. Participants who have RT-PCR-
positive SARS-CoV-2 infection will be monitored until they clinically recover (and if requested by local regulations, have negative RT-PCR results on two sequential samples 
taken at least 24 hours apart). Participants who are negative for SARS-CoV-2 RT-PCR will return to their respective study schedule. The COVID-19 Illness Visit may be 
conducted as an in-person visit or telehealth visit. In the case of telehealth visit, a qualified site staff will visit participant’s home or place of sojourn. 

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2. INTRODUCTION 
S-268019-b is a recombinant protein subunit vaccine being developed by Shionogi & 
Co., Ltd. for prevention of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-
2. S-268019-b consists of S-910823, a recombinant protein modified from SARS-CoV-2 
spike glycoprotein (S-protein) as an antigen and A-910823, squalene-in-water emulsion 
as an adjuvant. 
2.1 
Study Rationale 
This study will assess the efficacy, safety and immunogenicity of S-268019-b, a 
candidate prophylactic vaccine for the prevention of COVID-19. This study was planned 
to use the dose at which immunogenicity and safety were confirmed in the ongoing Phase 
1/2 double-blind study of S-268019-b (2026U0221). 
2.2 
Background 
COVID-19 was first identified in Wuhan, China, in December 2019, and has spread 
rapidly and globally. World Health Organization (WHO) expressed that COVID-19 could 
be characterized as a pandemic on March 11, 2020. Although most people infected by 
SARS-CoV-2 are asymptomatic or have mild symptoms, COVID-19 can also cause 
severe illness and even death. Some populations, including older adults and people who 
have certain underlying medical conditions, are at increased risk of severe illness. 
Globally, at the time of writing (July 2022), there have been more than 548 million 
confirmed cases of COVID-19, including 6 million deaths, reported to WHO [1]. 
SARS-CoV-2 is an enveloped β-coronavirus with a positive-sense, single-stranded RNA 
genome. The viral envelope is coated by S-protein, envelope, and membrane proteins [2]. 
The first step in infection is the virus binding to a host cell through its target receptor 
angiotensin-converting enzyme 2 (ACE 2). The S1 subunit of the S-protein contains the 
receptor binding domain that binds to the peptidase domain of ACE 2. The S2 subunit of 
the S-protein mediates fusion of the viral and host cell membranes, then the viral genome 
is delivered into the host cell [3]. The S2 subunit is highly preserved and is considered a 
target of vaccines against SARS-CoV-2.  
Vaccines are critical tools to settle down COVID-19 pandemic. Many COVID-19 
vaccines based on different technology platforms have been developed including 
inactivated vaccines, protein subunit vaccines, nucleic acid vaccines and viral vector 
vaccines. To date, five COVID-19 vaccines have been approved in the United States (US) 
or European Union (EU); tozinameran (Pfizer/BioNTech), mRNA-1273 (Moderna), 
Vaxzevria (AstraZeneca), Ad26.COV2.S (Johnson & Johnson) and Nuvaxovid 
(Novavax). The first two are messenger ribonucleic acid (mRNA) vaccines, the next two 
are adenovirus vector vaccines, and the last one is a recombinant protein vaccine. These 
vaccines have been shown vaccine efficacy compared to placebo in clinical studies.  
As COVID-19 vaccines rollout, risks of individual vaccines have become clear. 
Myocarditis or pericarditis have been reported after vaccination with mRNA vaccines 
especially in young males [4]. For adenovirus vaccines, vaccine-induced immune 

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thrombotic thrombocytopenia (VITT) or thrombosis with thrombocytopenia syndrome 
(TTS) have been reported especially in young female [5]. Incidences of these significant 
adverse reactions are very rare, and health authorities conclude that the benefits of 
COVID-19 vaccines outweigh the potential risks. That being said, these potential risks 
are a barrier to expanded immunization of COVID-19 vaccines to younger people.  
Thus, there is an urgent need to speed up the development of additional safe and effective 
vaccines against COVID-19 and provide them to all countries so that the world is 
effectively protected against COVID-19. 
S-268019-b is an investigational vaccine for the prevention of the COVID-19. 
S-268019-b consists of S-910823, a modified recombinant S-protein produced in insect 
cells using the baculovirus expression vector system (BEVS) [6] as an antigen, and 
A-910823 (including squalene, tocopherol and polysorbate 80 as main components) as an 
adjuvant. A detailed description of the physical, chemical and pharmaceutical properties 
of S-268019-b is provided in the Investigator’s Brochure [7]. 
As of July 8, 2022, in addition to this study, three clinical studies of S-268019-b as a 
priming vaccine are ongoing. In a phase 1/2 study (2026U0221), the safety, tolerability 
and immunogenicity of S-268019-b in Japanese adult participants are assessed. It was 
confirmed that there were no significant concerns with the safety and tolerability of 
S‑268019-b 5 µg and 10 µg up to Day 50 (28 days after the second vaccination). In the 
phase 1/2 study, the anti-spike protein IgG antibody titer and the neutralizing antibody 
titer were found to be produced up to Day 50 and 10 µg was selected as the dose in 
further studies. In a phase 2/3 study (2114U0222) and a phase 3 study (2025U0231), the 
immunogenicity, safety, and clinical efficacy of S-268019-b are to be assessed. In 
addition, a phase 2/3 study in participants aged 12 to 19 years (2148U0225) has been 
initiated. Furthermore, a phase 2/3 study (2124U0223) and a phase 3 study (2140U0224) 
to evaluate the immunogenicity of S-268019-b as a booster vaccine is ongoing. 
2.3 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of S-268019-b can be found in the Investigator’s 
Brochure [7]. 
 
 
 

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3. OBJECTIVES AND ENDPOINTS 
The study objectives and endpoints are shown in Table 3-1. 
Table 3-1 
Study Objectives, Estimands and Endpoints 
Objectives 
Estimands/Endpoints 
Primary 
● To assess the efficacy of a 2-dose regimen of 
S-268019-b for the prevention of COVID-19 
in the Initial Vaccination Period prior to 
crossover in participants without evidence of 
infection before vaccination as compared to 
placebo. 
Population: Modified Intent to Treat (mITT) 
Population 
Endpoint: The first occurrence of SARS-CoV-2 
reverse transcription polymerase chain reaction (RT-
PCR)-positive symptomatic COVID-19 in the Initial 
Vaccination Period (ie, prior to crossover), with onset 
at least 14 days following the second vaccination in 
participants seronegative and PCR-negative at 
baseline. 
Intercurrent events: For participants who withdraw 
from the study prior to having met the criteria for the 
primary efficacy endpoint, the absence of data 
following these participants’ withdrawal will be 
treated as missing; participants who withdrew before 
14 days post second vaccination or who were 
diagnosed with SARS-CoV-2 infection prior to 14 
days post second vaccination in the Initial 
Vaccination Period will be excluded from the primary 
endpoint analysis. 
Summary measure: Vaccine efficacy (VE), 
calculated as 1-relative risk. (Relative risk is the 
incidence of infection in the intervention group 
relative to the incidence of infection in the control 
group.) 
Key Secondary 
● To assess the efficacy of S-268019-b for the 
prevention of symptomatic infection of 
COVID-19 as compared to placebo. 
● The first occurrence of SARS-CoV-2 RT-PCR-
positive severe COVID-19 in the Initial 
Vaccination Period with onset at least 14 days 
following the second vaccination in participants 
seronegative and PCR-negative at baseline.  
● The first occurrence of SARS-CoV-2 RT-PCR-
positive symptomatic COVID-19 in the Initial 
Vaccination Period in participants seronegative and 
PCR-negative at baseline. 
● The first occurrence of SARS-CoV-2 RT-PCR-
positive severe COVID-19 in the Initial 
Vaccination Period in participants seronegative and 
PCR-negative at baseline.  

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Secondary 
● To assess the efficacy of S-268019-b for the 
prevention of symptomatic infection of 
COVID-19 as compared to placebo. 
● The first occurrence of SARS-CoV-2 RT-PCR-
positive symptomatic COVID-19 in the Initial 
Vaccination Period with onset at least 14 days 
following the second vaccination in participants 
regardless of serostatus or PCR status at baseline. 
● The first occurrence of SARS-CoV-2 RT-PCR-
positive severe COVID-19 in the Initial 
Vaccination Period with onset at least 14 days 
following the second vaccination in participants 
regardless of serostatus or PCR status at baseline.  
● The first occurrence of SARS-CoV-2 RT-PCR-
positive symptomatic COVID-19 in the Initial 
Vaccination Period in participants regardless of 
serostatus or PCR status at baseline. 
● The first occurrence of SARS-CoV-2 RT-PCR-
positive severe COVID-19 in the Initial 
Vaccination Period in participants regardless of 
serostatus or PCR status at baseline.  
● To assess the efficacy of a 2-dose regimen of 
S-268019-b for the prevention of 
asymptomatic infection of COVID-19 in 
participants without evidence of infection 
before vaccination. 
● The first occurrence of asymptomatic SARS-CoV-
2 infection in the Initial Vaccination Period 
beginning 14 days following the second 
vaccination in participants seronegative and PCR-
negative at baseline. Antibodies to SARS-CoV-2 
N-protein will be used to determine natural 
infection and to determine the incidence of 
asymptomatic infection acquired during study 
follow-up. 
● To assess the safety and reactogenicity of 
S-268019-b. 
● The incidence of AEs, treatment-related AEs, 
SAEs, AESIs, MAAEs, solicited local AEs, and 
solicited systemic AEs, and vital signs in the Initial 
Vaccination Period and the Crossover Vaccination 
Period. 
● To assess the immunogenicity of a 2-dose 
regimen of S-268019-b in the subset of 
immunogenicity subset. 
● The following items for SARS-CoV-2 neutralizing 
antibody titer and anti-SARS-CoV-2 S-protein 
immunoglobulin G (IgG) antibody titers from 
Immunogenicity subset: 
– Geometric mean titer (GMT) 
– Geometric mean of fold rise of antibody titer 
(GMFR) 
– Seroconversion rate 
Exploratory 
● To assess the durability of VE in the 
Crossover Vaccination Period. 
● The first occurrence of SARS-CoV-2 RT-PCR-
positive symptomatic COVID-19 in the Crossover 
Vaccination Period. 
● The first occurrence of asymptomatic SARS-CoV-
2 infection in the Crossover Vaccination Period. 
Antibodies to SARS-CoV-2 N-protein will be used 
to determine natural infection and to determine the 
incidence of asymptomatic infection acquired 
during study follow-up. 

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● To explore SARS-CoV-2 genetic variants in 
participants diagnosed with COVID-19. 
● Nucleotide sequences of SARS-CoV-2 viral 
genomes detected in nasopharyngeal swabs from 
RT-PCR-positive participants analyzed with next-
generation sequencing.  
 
4. STUDY DESIGN 
4.1 
Overall Design 
This is a multicenter, randomized, observer-blind, placebo-controlled, cross-over phase 3 
study to evaluate the efficacy, safety, and immunogenicity of S-268019-b in participants 
≥ 18 years of age. Participants, investigators, and other site staff except persons in charge 
of management, dispensing and administration of the study interventions will be blinded. 
This study will consist of the Screening Period (Day −28 to Day 1), the Initial 
Vaccination Period (Day 1 to Day 224), and the Crossover Vaccination Period (Day 225 
to Day 435). A schematic overview of the study is presented in Figure 1-1. 
In the screening period, potential participants who signed the informed consent form 
(ICF) will be screened for study participation. On Day 1 in the Initial Vaccination Period, 
eligible participants will be randomly assigned to either the S-268019-b-preceding group 
or the placebo-preceding group in a 2:1 ratio. A total of approximately 54,915 
participants will be randomized (36,610 participants in the S-268019-b-preceding group, 
18,305 participants in the placebo-preceding group). The randomization will be stratified 
by age group (18 to 64 years of age and ≥ 65 years of age). The group allocation and 
vaccination schedule are shown in Table 4-1. Participants assigned to the S-268019-b-
preceding group will receive S-268019-b on Day 1 and Day 29, and participants assigned 
to the placebo-preceding group will receive placebo on the same schedule. The Initial 
Vaccination Period will go on for 6 months after the second vaccination.  
 
Table 4-1 
Group Allocation and Vaccination Schedule 
Group 
Sample 
size 
Intervention in the Initial 
Vaccination Period 
Intervention in the Crossover 
Vaccination Period 
Day 1 
Day 29 
Day 225 
Day 253 
S-268019-b-preceding 
group  
36,610 
S-268019-b 0.5 mL 
Placebo 0.5 mL 
Placebo-preceding 
group 
18,305 
Placebo 0.5 mL 
S-268019-b 0.5 mL 
 
Participants who completed the Initial Vaccination Period without being infected with 
SARS-CoV-2 will proceed to the Crossover Vaccination Period starting on Day 225. In 
the Crossover Vaccination Period, participants assigned to the S-268019-b-preceding 
group will receive placebo on Day 225 and Day 253 and participants assigned to the 
placebo-preceding group will receive S-268019-b on the same schedule. The Crossover 
Vaccination Period will go on after the fourth vaccination to monitor for COVID-19-
related symptoms and to monitor for safety.  

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Participants will be assessed for the efficacy, safety, and immunogenicity in accordance 
with the planned schedule of activities (SoA, Table 1-3). Surveillance for COVID-19-
related symptoms during the study will be performed using e-Diary. Participants will be 
asked to record occurrence of COVID-19-related symptoms in e-Diary once a week. The 
investigator or designee will receive an alert e-mail from the e-Diary system when a 
participant reports any COVID-19-related symptom or a participant reports symptoms 
that meet the criteria for COVID-19. Then the investigator or designee instructs the 
participant to visit the site as soon as possible but no later than 3 days from that day to 
collect a nasopharyngeal swab sample for reverse transcription polymerase chain reaction 
(RT-PCR) test. The participants will undergo the procedures described in the SoA (Table 
1-4). The investigator should monitor a participant on a daily basis with information from 
e-Diary until RT-PCR result is available. The investigator should schedule additional site 
visit(s) or telehealth visit(s) depending on each participant’s condition and perform 
additional examination as appropriate. After RT-PCR result is available, the participant 
with a negative RT-PCR result will return to his/her respective study schedule. On the 
other hand, the RT-PCR-positive participants will be further monitored until they recover 
from COVID-19. The COVID-19 Follow-up Visit is scheduled 28 days after the Potential 
COVID-19 Illness Visit. If any COVID-19-related symptom persists at the time of the 
COVID-19 Follow-up Visit, the investigator should continue the follow-up until the 
participant has fully recovered or been medically stable. For participants who are 
diagnosed with COVID-19 before receiving the final vaccination, the subsequent 
vaccination will be cancelled, although they will continue to be assessed for the safety.  
Participants may undergo any diagnostics test for SARS-CoV-2 outside the study. 
Participants will be instructed to contact the site immediately when he/she obtains a result 
indicative of SARS-CoV-2 infection from such a test done outside the study. The 
investigator should assess if such results are suggestive of COVID-19 and arrange the 
confirmatory RT-PCR test as described above. 
4.2 
Scientific Rationale for Study Design 
This study is designed to evaluate primarily the clinical efficacy and safety of S-268019-b 
in the prevention of COVID-19. Well-designed clinical studies are necessary to 
determine the benefit and risk of a new vaccine. A randomized, observer-blind, and 
placebo-controlled study is a standard for phase 3 studies of investigational vaccines. 
In addition to the short-term safety and efficacy data, it is important to continue to follow 
up participants to provide the long-term safety and efficacy information of an 
investigational vaccine. On the other hand, there is argument from ethical viewpoint 
against including a placebo arm in a long-term blinded study. In order to address this 
issue, a blinded crossover design is adopted in this study. All participants assigned to 
placebo in the Initial Vaccination Period will receive the investigational vaccine in the 
Crossover Vaccination Period. All participants assigned to the investigational vaccine in 
the Initial Vaccination Period will receive placebo in the Crossover Vaccination Period. 
This crossover design ensures that all participants receive the investigational vaccine 
without unblinding the treatment assignment. Furthermore, the blinded crossover design 
enables estimation of durability of vaccine efficacy by assuming that the benefit of 

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vaccination over time has the same profile for the original vaccine recipients and the 
placebo crossovers [8]. 
The primary efficacy endpoint in this study is the first occurrence of SARS-CoV-2 RT-
PCR-positive symptomatic COVID-19 in the Initial Vaccination Period, with onset at 
least 14 days following the second vaccination in participants seronegative and PCR-
negative at baseline. Laboratory-confirmed COVID-19 is an acceptable primary endpoint 
for a COVID-19 vaccine phase 3 studies [9]. The vaccine efficacy will be estimated 
based on the primary endpoint. 
4.3 
Justification for Dose 
The dose of S-268019-b in this study was selected based on the results from the 
preceding double-blind phase 1/2 study of S-268019-b (2026U0221). In the preceding 
phase 1/2 study, an increase in SARS-CoV-2 neutralizing antibody (NAb) titers that 
could be expected to prevent the onset of COVID-19 was observed at the dose selected 
for this study, and there were no safety or tolerability concerns. 
4.4 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all 
periods of the study including the last visit. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 

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5. STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
Age 
1. Participant must be ≥ 18 years of age, at the time of signing the informed consent 
form. 
 
Sex 
2. Male and female 
a. Male 
There is no contraceptive obligation. 
b. Female: 
● A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and at least one of the following conditions applies: 
– Is not a WOCBP. 
OR 
– All of the following apply: 
▪ Is a WOCBP and using an acceptable contraceptive method 
described in Section 10.3, from the first dose of study 
intervention through at least 90 days after the last dose of study 
intervention. The investigator should evaluate the potential for 
contraceptive method failure (eg, noncompliance, recently 
initiated) in relationship to the first dose of study intervention. 
▪ A WOCBP must have a negative highly sensitive pregnancy 
test ([urine or serum] as required by local regulations) during 
the screening period before the first dose of study intervention 
(see Section 10.3). 
▪ If a urine pregnancy test cannot be confirmed as negative (eg, 
an ambiguous result), a serum pregnancy test to rule out 
positivity is required. 
● Additional requirements for pregnancy testing during and after study 
intervention are noted in Section 10.3. 
● The investigator or subinvestigator reviews medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a 
woman with an early undetected pregnancy. The investigator or 
subinvestigator excludes any woman considered potentially pregnant. 

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Informed Consent 
3. Capable of giving signed informed consent form as described in Section 10.1.3 
which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol. 
 
Other Inclusion 
4. Agree not to participate in any other SARS-CoV-2 prevention trial during the study 
follow-up. 
5. Capable of using Diary without difficulties (if applicable, with assistance by 
caregiver). 
 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Current or history of a laboratory-confirmed diagnosis of SARS-CoV-2 infection or 
COVID-19.  
2. Unstable current cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematological, or neurological disease that, in the opinion of the 
investigator or subinvestigator, would constitute a safety concern or confound data 
interpretation.  
3. Immunosuppression (immunodeficiency, acquired immunodeficiency syndrome 
[AIDS], use of systemic steroids, use of immunosuppressants within the past 6 
months prior to the first dose of study intervention, treatment for malignant tumors, 
other immunosuppressive therapy). 
4. Individuals considered to have hypersensitivity to any of the study interventions or 
components thereof, or drug or other allergy that, in the opinion of the investigator or 
subinvestigator, contraindicates participation in the study (except for pollinosis and 
atopic dermatitis). 
5. Participant has a contraindication to intramuscular (IM) injections or blood draws. 
 
Prior/Concomitant Therapy 
6. Previous vaccination against SARS-CoV-2. 
7. Any inactivated vaccine received within 14 days prior to the first dose of study 
intervention. 
8. Any live vaccine received within 28 days prior to the first dose of study intervention. 
9. Immunoglobulin preparations, blood products, or a blood transfusion within 3 
months prior to the first dose of study intervention. 
 

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Prior/Concurrent Clinical Study Experience 
10. Current enrollment or past participation within the last 30 days before signing of the 
ICF for this study in any other clinical study involving an investigational study 
intervention or any other type of medical research. 
11. Exposure to 4 or more new chemical entities within 12 months prior to the first dose 
of study intervention. 
 
Other Exclusions 
12. Ineligibility for the study as considered by the investigator or subinvestigator. 
13. An immediate family member or household member of this study’s personnel (both 
the sponsor and site personnel). 
 
5.3 
Lifestyle Considerations 
1. Participants must follow the contraception requirements outlined in Section 10.3. 
2. Refer to Section 6.5 for prohibited and restricted prior and concomitant therapy. 
3. Participants must keep their e-Diary as per instructions. 
 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomly assigned to study intervention. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.  
6. STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to, or used by, a study 
participant according to the study protocol. 
6.1 
Study Intervention(s) Administered 
Outlines of the study interventions are summarized in Table 6-1. Since S-268019-b and 
placebo are distinguishable by appearance, a pharmacist to prepare study vaccines and a 
vaccine administrator will be unblinded. The unblinded pharmacist and vaccine 
administrator must not communicate with participants, investigators, or other site staff 
about participant’s treatment assignment. 

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Table 6-1 
Study Intervention(s) 
 
Test Vaccine 
Placebo 
Study Intervention 
Name 
S-268019 solution for 
intramuscular injection 
(containing S-910823) 
40 µg/mL 
S-268019 oil-in-water 
emulsion adjuvant 
Placebo (physiological 
saline) 
Dosage formulation Solution for IM injection 
Emulsion for IM injection Solution for IM injection 
Container 
Vial 
Vial 
Prepared locally by a 
qualified site personnel 
Filling volume 
Each vial contains 2 
doses of 0.25 mL. 
Each vial contains 2 
doses of 0.25 mL. 
Prepared locally by a 
qualified site personnel 
Dosage level(s) 
One dose contains 10 μg 
of S-910823 (antigen) in 
0.25 mL 
Each vial contains 1 mL 
of A-910823 (for the 
Initial Vaccination 
Period) 
Each vial contains 0.9 mL 
of A-910823 (for the 
Crossover Vaccination 
Period) 
Placebo 
Dosage and 
Administration 
S-268019 solution for IM injection (containing 
S-910823) 40 μg/mL and S-268019 oil-in-water 
emulsion adjuvant are mixed at a ratio of 1:1 (each 
0.25 mL for one dose), and 0.5 mL of the mixture is 
administered at a 4-week interval for a total of two 
doses. 
A dose of 0.5 mL is 
administered at a 4-week 
interval for a total of two 
doses. 
Route of 
Administration 
IM injection 
Use 
Investigational vaccine 
(antigen) 
Investigational vaccine 
(adjuvant) 
Placebo as comparator 
IMP and NIMP 
IMP 
IMP 
IMP 
Sourcing 
Provided centrally by the sponsor 
Prepared locally by a 
qualified site personnel 
Packaging and 
Labeling 
Study intervention will be provided in vials. Each vial 
will be labeled as required per country requirement. 
Not applicable 
IM = intramuscular; IMP = investigational medicinal product; NIMP = non-investigational medicinal 
product 
 
The vaccination should be given in the upper arm and, if a solicited local adverse event 
(see Section 8.4.6) occurs after the vaccination, the next vaccination of study intervention 
may be given in an arm different from that receiving the previous vaccination. 
 
S-268019-b 
The investigational vaccine used in this study is composed of S-268019 solution for IM 
injection (containing S-910823) 40 μg/mL as an antigen and S-268019 oil-in-water 
emulsion adjuvant (A-910823). S-910823 is a recombinant protein modified from 

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S-protein of SARS-CoV-2. A-910823 is squalene-in-water emulsion. S-910823 and 
A-910823 are supplied in different vials. The vaccine (ie, S-268019-b) is a 1:1 mixture of 
antigen and adjuvant. Please refer to the study vaccine manual for instructions on how to 
prepare the study vaccine. 
Placebo 
Commercially available 0.9% (w/v) physiological saline for injection will be used for 
placebo. Placebo will be sourced locally. 
6.2 
Preparation/Handling/Storage/Accountability of Study 
Intervention 
1. Before unblinding the assignment of participants to the intervention groups at the 
time of the primary immunogenicity analysis, the unblinded pharmacist or designee 
will maintain accurate records of the following information; receipt and condition of 
all study drugs, date of the receipt, when and how much the study intervention was 
dispensed and administered to each participant in the study, date and time of 
reconstitution, and any reasons for departure from the protocol-defined regimen. The 
unblinded pharmacist or designee must confirm that appropriate temperature 
conditions have been maintained during transit for all study interventions received 
and any discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff. 
3. The drug accountability records and the used vials should be available for verification 
by the unblinded sponsor monitor, unblinded contract research organization (CRO), 
or designee at each monitoring visit as specified in the unblinded clinical operations 
plan. If the local procedures at a site require immediate disposal of used vials, an 
alternative process for drug accountability will be made with the site and the process 
will be documented in the study files.  
4. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
5. Further guidance and information for the final disposition of unused study 
interventions are provided in the Pharmacy Manuals.  
 
6.2.1 
Dose Preparation and Dispensing 
All study interventions must be stored in a secured location with limited access and at 
controlled temperatures as indicated on the product labels. If a study intervention is 
exposed to temperatures outside the specified temperature range, all relevant data will be 
sent to the sponsor to determine if the affected supplies can be used or will be replaced. 

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The affected study intervention must be quarantined and not used until further instruction 
from the sponsor is received. 
Doses of S-268019-b and placebo will be prepared by an unblinded pharmacist at the 
study site, who will not be involved in any other study procedures. The unblinded 
pharmacist will obtain the treatment assignment information from an Interactive Web 
Response System (IWRS) at Days 1, 29, 225 and 253, and draw S-268019-b or placebo 
into a syringe labeled with the participant’s identification number. The unblinded 
pharmacist will provide the syringe to an unblinded vaccine administrator. The unblinded 
pharmacist and administrator must not communicate with the investigator or other site 
staff about the participant treatment assignment. 
6.2.2 
Administration 
Participants will visit the study sites and receive one dose of study intervention at each 
vaccination visit (Days 1 and 29 in the Initial Vaccination Period and Days 225 and 253 
in the Crossover Vaccination Period). The investigator or designee should confirm 
participant’s eligibility for vaccination prior to each vaccination (see Section 6.2.3). 
Study intervention should be administered intramuscularly into the deltoid muscle, 
preferably of the nondominant arm, by an unblinded administrator. Participants will 
remain under observation by blinded site staffs for at least 30 minutes after each 
vaccination to monitor for the development of acute allergic reactions.  
6.2.3 
Criteria for Delay of Study Vaccination 
The investigator or subinvestigator should confirm that participants meet the following 
two conditions at the time of each vaccination. If either of the following conditions is not 
met, the vaccination on that day will be postponed. Out of window vaccination is allowed 
for this reason.  
1. 
Participants with axillary temperature < 37.5°C or oral temperature < 38.0°C  
2. 
Participants considered by the investigator or subinvestigator to have no problems 
with vaccination 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Randomization 
All participants will be centrally assigned to randomized study intervention using an 
IWRS. The randomization will be stratified by age group (18 to 64 years of age and ≥ 65 
years of age). Before the study is initiated, the login information and directions for the 
IWRS will be provided to each site. 
Study intervention will be dispensed at the study visits summarized in the SoA (Table 
1-3). The IWRS will be responsible for the allocation of randomization numbers to 
individual participants. Randomization will take place on Day 1 in the Initial Vaccination 
Period after the investigator confirms that a participant is eligible for the study. 
Participants will be randomized to either the S-268019-b-preceding group or the placebo-

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preceding group in a 2:1 ratio. At the time of blinded crossover (Day 225), the IWRS 
system will assign participants to the alternative treatment from that which they received 
in the Initial Vaccination Period.  
6.3.2 
Blinding 
This is an observer-blind study and study intervention is blinded to the participants, 
investigators, subinvestigators, site staff who are not involved in preparation and 
administration of the study intervention. The sponsor, and the sponsor’s designees 
involved in blinded monitoring, data management, or other aspects of the study will be 
kept blinded to the allocation of S-268019-b and placebo. The Independent Data 
Monitoring Committee, unblinded staff involved in the assessment of safety, and 
unblinded clinical monitors will be unblind. Also, the site pharmacist or qualified 
designee who will prepare the solution will be unblinded so that he/she may obtain the 
assigned study intervention and prepare the dosing solutions. Procedures for maintaining 
blinding will be specified separately.  
The IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
participant’s intervention assignment is warranted. The investigator should get the 
participant’s intervention assignment information from IWRS, but not from the site 
unblinded pharmacist or qualified designee. Participant safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding 
is warranted, the investigator should make every effort to contact the sponsor prior to 
unblinding a participant’s intervention assignment unless this could delay emergency 
treatment for the participant. If a participant’s intervention assignment is unblinded, the 
sponsor must be notified within 24 hours after breaking the blind. The date and reason 
that the blind was broken must be recorded in the source documentation and IWRS, as 
applicable. 
If investigators receive requests to unblind study participants who become eligible to 
receive an authorized/licensed COVID-19 vaccine, the investigator will discuss with the 
participant available options and ramifications. If the participant is eligible for an 
authorized/licensed vaccine according to local immunization guidelines or 
recommendation and if the participant wishes to proceed with the unblinding, the 
investigator will follow the unblinding procedures. The reason for the unblinding request 
should be documented. The name and dates of administration of the other COVID-19 
vaccine should be recorded. When unblinding, if it is determined that the participant 
received S-268019-b, the participant will be informed that there are not sufficient data on 
the safety of receiving other COVID-19 vaccines in addition to S-268019-b. Unblinded 
participants, whether in the S-268019-b-preceding group or placebo-preceding group, 
will be asked to continue to be followed in this study in line with the schedule of 
activities to the extent that they permit. Efficacy and safety evaluations will be identical 
for all participants, including participants that are unblinded to obtain an 
authorized/licensed COVID-19 vaccine and who remain in the study, including 
participants in the safety subset, if applicable and feasible. All data will be analyzed 

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separately from the point of unblinding, for safety and efficacy analysis, as described in 
the Statistical Analysis Plan. 
 
6.4 
Study Intervention Compliance 
The unblinded vaccine administrator will administer the study intervention to participants 
at the study sites. The date and time of each vaccination will be recorded in the source 
documents and the date will be recorded in the electronic case report form (eCRF). Study 
participant identification will be confirmed at the time of dosing by the study site staff 
other than the vaccine administrator.  
The investigator or site staff should have participants visit the study site within the 
specified visit windows. If a participant doesn’t come to the study site on an appointed 
day, every effort should be made to contact the participant and complete a visit within the 
specified visit window. The vaccination will not be cancelled even if a participant comes 
to the study site outside the time window. 
6.5 
Prior Therapy/Concomitant Therapy 
Prior therapies (prior medications/therapies) are those taken prior to the first dose of 
study intervention (prescription medications, over-the-counter medications/herbal 
medicines, and non-drug therapies). Restrictions regarding prior therapies are specified in 
the exclusion criteria. 
Concomitant therapies (concomitant medications/therapies) are those taken after the first 
dose of study intervention until the time of the end-of-study/early discontinuation 
examination (prescription medications, over-the-counter medications/herbal medicines, 
and non-drug therapies). 
 
Prohibited Concomitant Medications/Therapies 
The use of following medications/therapies will be prohibited from the time of informed 
consent to Day 435 or completion of the tests at discontinuation. 
● SARS-CoV-2 vaccine 
● Corticosteroids (oral, injection, suppository, or enema only) 
● Immunosuppressants (oral, injection, suppository, or enema only) 
● Any other investigational study intervention 
Even if a participant takes a prohibited medication, the participant will continue the study 
and undergo the scheduled examinations. 
When the latest information on the S-268019-b is obtained, the investigator or designee 
will provide the information to participants and recommend an authorized/approved 
vaccine to participants, considering safety information. If participants wish receipt of an 
authorized/approved vaccine depending on the information, the investigator or designee 

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will consider safety and make a decision whether these participants can get an 
authorized/approved vaccine. In that case, the participant must discontinue the study 
intervention. And if the participant could not get the second dose of study intervention, 
the participant must discontinue the study participation.  
Restricted Concomitant Medications/Therapies 
The use of following medications/therapies will be prohibited from the time of informed 
consent to completion of the tests to be performed on Day 253. 
● Non-SARS-CoV-2 vaccines 
● Blood-derived immunoglobulin preparations 
● Blood products 
● Transfusions 
All prior therapies used/administered within 7 days prior to the first dose of study 
intervention and all concomitant therapies (prescription medications, over-the-counter 
medications, and non-drug therapies) used by participants at the time of study 
intervention during study period must be recorded except during Day 58 to 224 and 
Day 254 to 435, in which only concomitant medication for treatment of SAE, MAAE, or 
AESI, or prohibited medication will be collected. These therapies are recorded in the 
eCRF along with: 
● Reason for use 
● Dates of use including start and end dates 
● Route of administration 
The sponsor should be contacted if there are any questions regarding acceptable 
concomitant or prior therapy. 
6.6 
Dose Modification of Study Intervention 
This protocol allows neither dose modification nor changes to the number of doses of the 
study intervention.  
6.7 
Intervention after the End of the Study 
No medical/vaccination intervention for the prophylaxis of COVID-19 will be provided 
to study participants at the end of the study. 
 
7. DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Discontinuation of specific sites or of the study as a whole are handled as part of Section 
10.1.9. 

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7.1 
Discontinuation or Suspension of Entire Study and Participant 
Discontinuation or Suspension 
7.1.1 
Discontinuation or Suspension of the Entire Study 
The sponsor may prematurely terminate or suspend the entire study for the following 
reason: 
● Ensuring safety of the study is difficult due to safety concerns (eg, occurrence of 
many serious treatment-related AEs) 
 
7.1.2 
Discontinuation or Suspension of Individual Participants 
Participants will be discontinued from the study if any of the following criteria are met: 
At the time of discontinuing from the study participation, an early discontinuation 
examination should be conducted as far as possible, as shown in the SoA. Refer to the 
SoA (Section 1.3) for data to be collected at early discontinuation. If possible, collection 
of safety data will be continued from participants who discontinue from the study 
participation after administration of study intervention. 
 
Criteria for Discontinuation of Study Participation 
● The participant requests to discontinue study participation 
● The participant is lost to follow-up 
● The participant died 
● The participant meets the criteria for discontinuation of study intervention after 
the first vaccination and could not receive the second dose of study intervention 
● The investigator or subinvestigator considers that the participant should be 
withdrawn from study participation for any other reasons 
 
Criteria for Discontinuation of Study Intervention after the First Vaccination 
● The participant is found to be infected with SARS-CoV-2 based on the RT-PCR 
test at the Potential COVID-19 Illness Visit. However, if the participants who are 
infected with SARS-CoV-2 after second dose wish to receive the study 
intervention in the Crossover Vaccination Period and the investigator or 
subinvestigator considers that they have no problems with vaccination on Day 225 
and Day 253, they will be able to receive the study intervention and continue the 
study schedule. 
● The participant received any approved SARS-CoV-2 vaccine 
● The participant became pregnant 
● A serious or intolerable AE occurs after the first dose of study intervention and 
the investigator or subinvestigator considers that the further study intervention 
should be discontinued 

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● Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 8 × Upper 
limit of normal (ULN) 
● ALT or AST ≥ 5 × ULN but < 8 × ULN persists for ≥ 2 weeks, or ALT or 
AST ≥ 3 × ULN but < 5 × ULN persists for ≥ 4 weeks 
● ALT or AST ≥ 3 × ULN AND total bilirubin ≥ 2 × ULN (direct bilirubin > 35%) 
● ALT or AST ≥ 3 × ULN AND prothrombin time-international normalized ratio 
(PT-INR) > 1.5, if PT-INR measured 
● ALT or AST ≥ 5 × ULN but < 8 × ULN and cannot be monitored weekly for ≥ 2 
weeks, or ALT or AST ≥ 3 × ULN but < 5 × ULN and cannot be monitored 
weekly for ≥ 4 weeks 
● ALT or AST ≥ 3 × ULN with appearance or worsening of symptoms believed to 
be related to liver injury or hypersensitivity 
 
Study intervention will be discontinued for a participant if liver chemistry stopping 
criteria are met. 
Figure 7-1 
Phase 3-4 Liver Chemistry Stopping Criteria and Increased 
Monitoring Algorithm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase, INR = international 
normalized ratio; SAE = serious adverse event, Tbili = Total bilirubin; ULN = upper limit of normal 
 
Plus 
Tbili ≥ 
2xULN 
(>35% direct) 
or plus 
INR>1.5*  
if measured 
➢
Must refer to Liver Safety Actions and Suggested Follow-up Assessments section in the 
Appendix 
➢
Report as an SAE if any of the following criteria apply: 
ALT or AST ≥3×ULN and total bilirubin ≥2×ULN (>35% direct) or INR >1.5*, if measured 
*INR value not applicable to subject on anticoagulants 

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Figure 7-2 
Phase 3-4 Liver Chemistry Increased Monitoring Algorithm 
with Continued Study Intervention for Participants with ALT 
or AST  3 × ULN but < 8 × ULN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase, INR = international 
normalized ratio; SAE = serious adverse event, Tbili = Total bilirubin; ULN = upper limit of normal 
 
Liver Safety: Suggested Actions and Follow-up Assessments can be found in Section 
10.5. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
● A participant may withdraw from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance, or administrative reasons. However, unless there is a 
safety reason, the participant should only be withdrawn from study drug 
administration, while continuing to remain in the trial and continuing to follow the 
SoA scheduled visits, even while off-vaccine to protect the integrity of the study 
and the participant’s well-being. 
● If the participant withdraws consent, the sponsor may retain and continue to use 
any data collected before such a withdrawal of consent. 
➢
Must refer to Liver Safety Actions and Suggested Follow-up Assessments section in the Appendix 
➢
Report as an SAE if any of the following criteria apply: 
ALT or AST ≥3×ULN and total bilirubin ≥2×ULN (>35% direct) or INR >1.5*, if measured 
*INR value not applicable to subject on anticoagulants 

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● If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
● At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA (Table 1-3). See the SoA for data 
to be collected at the time of study discontinuation and follow-up and for any 
further evaluations that need to be completed. The participant will be permanently 
discontinued both from the study intervention and from the study at that time. 
 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she fails to return for scheduled 
visits and is unable to be contacted by the site staff.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
● The site staff must attempt to contact the participant and reschedule the missed 
visit as soon as possible and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the 
participant wishes to and/or should continue in the study. 
● Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant by phone and the contact 
attempts should be documented in the participant’s medical record. 
● Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.  
 

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8. STUDY ASSESSMENTS AND PROCEDURES 
● Study procedures and their timing are summarized in the SoA (Table 1-3). 
Protocol waivers or exemptions are not allowed. 
● Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
● Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
● All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator must maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
● Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of the ICF may be utilized for screening 
or baseline purposes provided the procedures met the protocol-specified criteria 
and were performed within the time frame defined in the SoA. 
 
The investigator should investigate the following information according to the SoA 
(Section 1.3). The investigator or designee should record the result of investigation in the 
eCRF. 
– Demographics 
Year of birth, age at the time of signing the informed consent form, sex, 
ethnicity, race, smoking status, medical history (all complications 
persist at the time of signing the informed consent form, significant 
medical history requiring hospitalization or surgery within 12 months 
prior to signing the informed consent form) 
– Body measurement 
Height, body weight, body mass index (BMI) (automatically calculated 
by electronic data capture system [EDC]) 
 
8.1 
Assessment Tool 
8.1.1 
Electronic Clinical Outcome Assessment (e-Diary) 
An electronic clinical outcome assessment (e-Diary) tool will be used in this study. The 
e-Diary uses either an application downloaded to participant’s smartphone/tablet or a 
device that is provided to participants at the time of enrollment. The e-Diary tool will be 
provided in the local language. 
The e-Diary will be used for the following purposes. 
● To surveil COVID-19-related symptoms. 

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● To collect solicited local and systemic AEs during 7 days after the first and 
second vaccinations (e-Diary) 
On Day 1 and at the Potential COVID-19 Illness Visit, participants (or their caregiver, if 
applicable) will be trained on how to use the e-Diary tool. A user manual will be provided 
to participants. A Help Desk will be available for technical support. Participants who 
confirmed not to be able to use the e-Diary should use paper diaries. Those participants 
will be trained on how to use the paper diaries.   
8.2 
Efficacy Assessments 
In this study, the vaccine breakthrough cases will be investigated as an efficacy 
assessment. 
8.2.1 
Definition of Symptomatic COVID-19 
A patient is defined to have symptomatic COVID-19 when the patient’s RT-PCR test 
result is positive and he or she has at least one of the following COVID-19-related 
symptoms (Table 8-1). The medical monitor of the sponsor will confirm whether each 
potentially symptomatic patient has symptomatic COVID-19 or not. 
Table 8-1 
COVID-19-related Symptoms 
Duration 
Symptom 
No minimum duration 
Fever (Oral ≥ 38.0°C [≥ 100.4°F] 
or Axillary ≥ 37.5°C [≥ 99.5°F]) 
Shortness of breath 
Difficulty breathing 
Must be present for ≥ 2 days 
Chills 
Cough 
Fatigue 
Muscle aches 
Body aches 
Headache 
New loss of taste 
New loss of smell 
Sore throat 
Congestion 
Runny nose 
Nausea 

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Duration 
Symptom 
Vomiting 
Diarrhea 
Modified from Centers for Disease Control and Prevention (CDC) 2020 [10].  
8.2.2 
Severity of COVID-19 
If a participant is confirmed to have symptomatic COVID-19, the investigator will 
evaluate if the maximum intensity during the course of the disease meets the criteria for 
severe COVID-19. Severe COVID-19 is defined as any of the following conditions: 
● Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥ 30 
breaths per minute, pulse rate ≥ 125 beats per minute, oxygen saturation ≤ 93% on 
room air at sea level, or partial pressure of oxygen to fraction of inspired oxygen 
ratio < 300 mmHg) 
● Respiratory failure (defined as needing high-flow oxygen, noninvasive 
ventilation, mechanical ventilation or extracorporeal membrane oxygenation 
[ECMO]) 
● Evidence of shock (systolic blood pressure [SBP] < 90 mmHg, diastolic blood 
pressure [DBP] < 60 mmHg, or requiring vasopressors) 
● Significant acute renal, hepatic, or neurologic dysfunction 
● Admission to an intensive care unit (ICU) 
● Death 
The investigator will record the severity (severe or not), start and end dates, and the 
presence or absence of RT-PCR tests result outside the study sites (if performed) in the 
eCRF. The date of onset of COVID-19 is defined as the date when a symptom associated 
with COVID-19 is first reported. 
A hospitalization due to COVID-19 must be reported as an SAE (Section 10.2.4). Details 
of treatments/procedures in response to the SAE such as oxygenation, ventilation, transfer 
to an ICU should be described.  
8.2.3 
Surveillance for COVID-19-related Symptoms 
Surveillance of COVID-19-related symptoms will be performed throughout the study 
(after the first vaccination and until the end of the study) using an e-Diary tool. The e-
Diary uses either an application downloaded to participant’s smartphone/tablet or a 
device that is provided to participants at the time of enrollment. The e-Diary tool will be 
provided in the local language. 
On Day 1 and at the Potential COVID-19 Illness Visit, participants (or their caregiver, if 
applicable) will be trained on how to use the e-Diary tool. A user manual will be provided 
to participants. A Help Desk will be available for technical support. The questionnaire on 

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the e-Diary asks if a participant had any of COVID-19-related symptoms. Participants 
will complete the questionnaire for COVID-19-related symptoms at least once a week or 
whenever they experience any new or worsened COVID-19-related symptoms.  
The investigator or designee will receive an alert e-mail from the e-Diary system when a 
participant reports any COVID-19-related symptom. The investigator or designee will 
review the information in the e-Diary. If any COVID-19-related symptom (Table 8-1) is 
suspected, the investigator or designee will instruct the participant to visit the site for the 
Potential COVID-19 Illness Visit (Section 8.2.5.1) as soon as possible but within 3 days 
after the investigator or designee realizes the symptom. The investigator or designee 
records the date of instruction in the eCRF if they instruct participants to visit, and 
records the reason in the source record if they did not instruct a visit. If the e-Diary 
cannot be used for some reason, the investigator or site staff will instruct the participants 
to record the presence or absence of COVID-19-related symptoms on a paper diary, and 
instruct the participants at every visit to contact the study site promptly if they experience 
any new COVID-19-related symptoms. 
In addition, if the participant's condition suddenly changes, the investigator or 
subinvestigator should instruct the participant in advance so that the participant or the 
participant's family will notify the study site by telephone or the like. When notified by 
the participant or the participant's family, the investigator or subinvestigator will collect 
information about the participant's COVID-19-related symptoms. 
It should be noted that some of COVID-19-related symptoms overlap with solicited 
systemic AEs (ie, fever, chills, nausea/vomiting, diarrhea, headache, fatigue, myalgia). In 
principal, these events that occur during the 7 days following each vaccination should not 
trigger a Potential COVID-19 Illness Visit unless, in the investigator’s opinion, the 
clinical picture is more indicative of a possible COVID-19 illness than vaccine 
reactogenicity. 
8.2.4 
SARS-CoV-2 RT-PCR Test 
Nasopharyngeal swab samples will be collected before the first vaccination on Day 1 to 
determine a modified intent-to-treat (mITT) population and on Potential COVID-19 
Illness Visit for judgement of symptomatic COVID-19. The samples will be sent to 
central laboratories for the SARS-CoV-2 RT-PCR test. Instructions for obtaining mid-
turbinate nasopharyngeal swabs samples and shipping to the central laboratory are 
provided in the Laboratory Manual. The result will be reported to the study site after 
sample arrival at the central laboratory. The SARS-CoV-2 RT-PCR test on Day 1 and 
additional (qualitative or quantitative) PCR test may be performed at study sites or local 
laboratories in accordance with local regulations or institutional standards; however, the 
final diagnosis of SARS-CoV-2 infection after the vaccination must be based on the 
results from the central laboratory. 

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8.2.5 
Procedures in the Event of Suspected COVID-19  
8.2.5.1 
Potential COVID-19 Illness Visit 
At the Potential COVID-19 Illness Visit, a participant will undergo the procedures 
described in the SoA (Table 1-4). The Potential COVID-19 Illness Visit may be 
conducted as an in-person visit or telehealth visit. In the case of telehealth visit, a 
qualified site staff will visit participant’s home or place of sojourn. The RT-PCR test 
must be performed to confirm SARS-CoV-2 infection. The investigator or site staff will 
contact the participant once a result of the RT-PCR test is available. The participant with 
a negative RT-PCR result will return to his/her respective study schedule. On the other 
hand, the RT-PCR-positive participants will be further monitored until they recover from 
COVID-19. Participants will self-evaluate COVID-19-related symptoms and record in 
the e-Diary daily until all symptoms have disappeared. The investigator should carefully 
monitor a participant and give a participant adequate treatment in accordance with 
applicable local/international treatment guideline and/or institutional standard until the 
participant has fully recovered or been medically stable. 
8.2.5.2 
COVID-19 Illness Visit 
For a participant confirmed to have symptomatic COVID-19, the investigator should 
schedule additional site visit(s) or telehealth visit(s) depending on participant’s condition 
and perform additional examination as appropriate (this is referred to as “COVID-19 
Illness Visit”). Such additional examinations include physical examination, vital signs, 
peripheral capillary oxygen saturation (SpO2), blood gas analysis, chest X-ray or 
computed tomography (CT). If such additional tests are performed, the investigator will 
record the test results in the eCRF. 
8.2.5.3 
COVID-19 Follow-up Visit 
The participant confirmed to have COVID-19 will be monitored until he/she clinically 
recovers (and, if requested by local regulations, has negative RT-PCR results on two 
sequential samples taken at least 24 hours apart). The COVID-19 Follow-up Visit is 
scheduled 28 days after the Potential COVID-19 Illness Visit to confirm if the participant 
has fully recovered or has been medically stable. If any COVID-19-related symptom 
persists at the time of the COVID-19 Follow-up Visit, the investigator should continue 
the follow-up until the participant has fully recovered or been medically stable. 
8.2.6 
Definition of Asymptomatic COVID-19 
Asymptomatic SARS-CoV-2 infection is defined as a case in which a participant has 
positive result of anti-SARS-CoV-2 N-protein antibody test and does not meet the criteria 
of symptomatic COVID-19 (Section 8.2.1). For asymptomatic SARS-CoV-2 positive 
participants, Potential COVID-19 Illness Visit is not performed unless the participant 
reports COVID-19 symptoms. 
8.3 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Table 1-3). 

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For any abnormal findings of safety assessments (eg, physical examination, vital signs) 
that worsen following exposure to the study drug from baseline, the investigator will 
consider whether those results are clinically significant. Any test results which are 
considered to be clinically significant by the investigator are to be recorded as adverse 
events (AEs). If abnormal laboratory finding is associated with disease or organ toxicity, 
the investigator should report only the disease or organ toxicity as an AE.  
The investigator will consider test results to be clinically significant in the following 
circumstances (at their own discretion in the other circumstances): 
● Test results that lead to any of the outcomes included in the definition of a serious 
adverse event (SAE) (See Section 8.4). 
● Test results that lead to a dose interruption or discontinuation from the study. 
● Test results that lead to a concomitant drug treatment or other therapy. 
● Test results that require additional diagnostic testing (except for a confirmatory 
test) or other medical intervention. 
● Test results that meet the management and stopping criteria for abnormal liver 
function tests identified in Section 7.1 and 10.5. 
In addition, when any test results meet the management and stopping criteria for liver 
function abnormalities (Section 7.1 and Section 10.5) including tests conducted outside 
the study, the results of further assessments and required follow-up should be recorded in 
the Liver Event Form. 
8.3.1 
Physical Examinations 
A complete physical examination will be performed at screening followed by brief 
physical examinations as specified in the SoA (Table 1-3). 
● A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems.  
● A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
● Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
 
8.3.2 
Vital Signs 
Vital signs will be measured during the study as specified in the SoA (Table 1-3). 
● Body temperature (oral or axillary), pulse rate, respiratory rate, and blood 
pressure will be assessed. 
● Blood pressure and pulse rate measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is 
not available. 

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● Blood pressure and pulse rate measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (eg, 
television, cell phones). 
● Vital signs (to be taken before blood collection for immunogenicity assessments) 
will consist of 1 pulse rate and 1 blood pressure measurements.  
● In addition to vital signs mentioned above, SpO2 will be measured using a pulse 
oximeter during the COVID-19 Illness Visit (Table 1-4). It should be noted that 
multiple factors can affect the accuracy of a pulse oximeter reading, such as poor 
circulation, skin pigmentation, skin thickness, skin temperature, current tobacco 
use, and use of fingernail polish. 
 
8.3.3 
Pregnancy Test 
A pregnancy test (urine or serum as required by local regulations) for participants of 
childbearing potential will be performed at screening and when it is deemed necessary by 
the investigator or subinvestigator in the first 57 days of each period. 
Refer to Section 8.4.5 for the pregnancy reporting. Female participants who have a 
positive pregnancy test before the last vaccination of the study intervention should 
receive no further study intervention but should be followed-up for safety. 
8.4 
Adverse Events, Serious Adverse Events, Medically Attended 
Adverse Events and Adverse Events of Special Interest 
AEs reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative) must be captured in source documents.  
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE, SAE, medically attended adverse 
event (MAAE, see Section 8.4.7) or adverse event of special interest (AESI, see Section 
8.4.8) and remain responsible for following up AEs that are serious, considered related to 
the study intervention or study procedures, or that caused the participant to discontinue 
the study (see Section 7.2). 
8.4.1 
Time Period and Frequency for Collecting AE, SAE, MAAE and 
AESI Information  
AEs will be collected from the date of signing of the ICF to 4 weeks after the second 
vaccination (Initial Vaccination Period), and from the third vaccination to 4 weeks after 
the fourth vaccination (Crossover Vaccination Period). All SAEs, MAAEs and AESI will 
be collected from the date of signing of the ICF until end of the study. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under 
no circumstance should this exceed 24 hours, as indicated in Section 10.2.4. The 
investigator will report any updated SAE data to the sponsor within 24 hours of it being 
available. 

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Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study (out of period specified in 
SoA in Section 1.3), and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the sponsor. 
8.4.2 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 10.2. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrences.  
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is provided in 
Section 10.2.3. 
8.4.4 
Regulatory Reporting Requirements for SAEs 
● Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of participants 
and the safety of a study intervention under clinical investigation are met.  
● The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRBs)/Independent Ethics Committees (IECs), and investigators. 
● For all studies except those utilizing medical devices investigator safety reports 
must be prepared for suspected unexpected serious adverse reactions (SUSARs) 
according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
● An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (eg, summary or listing of SAEs) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate, according to local requirements. 
8.4.5 
Pregnancy 
● Details of all pregnancies in female participants will be collected from the first 
dose of study intervention through at least 90 days after the last dose of study 
intervention. 

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● If a pregnancy is reported, the investigator should inform the sponsor within 24 
hours of learning of the pregnancy and should follow the procedures outlined in 
Section 10.3. 
● Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 
8.4.6 
Reactogenicity 
The term “reactogenicity” refers to the property of a vaccine of being able to produce 
common solicited adverse reactions, especially excessive immunological responses and 
associated signs and symptoms. In order to assess the reactogenicity of S-268019-b, 
predefined solicited local and systemic AEs (Table 8-2) occurring after the first and 
second vaccinations and until 7 days post-vaccination will be collected using e-Diary.  
 
Table 8-2 
Solicited Local and Systemic Adverse Events 
Solicited Local Adverse Events 
Solicited Systemic Adverse Events 
● Pain 
● Erythema/Redness 
● Induration 
● Swelling 
● Fever (Oral >38.0°C [>100.4°F] or 
Axillary >37.5°C [>99.5°F]) 
● Nausea/Vomiting 
● Diarrhea 
● Headache 
● Fatigue 
● Myalgia 
 
Participants will record occurrences of the solicited AEs on the day of each vaccination 
and for the 7 days after vaccination, preferably on the same time each day. Severity of 
solicited AEs will be graded in accordance with the US FDA guidance: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials (Section 10.4) [11]. For erythema/redness, induration and swelling, 
participants will measure the longest diameter and record it in an e-Diary. For solicited 
systemic AEs and local pain, participants will self-evaluate the severity of the events. The 
investigator should review e-Diaries and enter the relevant information in the solicited 
AE form of the eCRF. If a solicited AE meets the criteria for SAEs or MAAEs, it should 
be reported as SAEs or MAAEs. If the e-Diary cannot be used for some reason, the 
investigator or site staff will instruct the participants to record the presence or absence of 
the solicited AEs and the severity of the events on paper diary. 
If a solicited local or systemic AE continues beyond 7 days after dosing, an outcome of 
such event will be recorded in the eCRF. The investigator or site staff will contact a 
participant by phone to follow-up the event.  

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8.4.7 
Medically Attended Adverse Events 
An MAAE is defined as an AE leading to medically-attended visits that were not routine 
study visits, for example, hospital, emergency room (ER), urgent care clinic, or other 
visits to or from medical personnel for an AE. AEs, including abnormal vital signs, 
identified on a routine study visit or during the scheduled illness visits will not be 
considered MAAEs. An MAAE can be serious or non-serious. All MAAEs will be 
recorded in the eCRF. Serious MAAEs will be recorded and reported as per Section 
8.4.4. 
8.4.8 
Adverse Events of Special Interest 
Potential immune-mediated diseases will be collected as AESIs of S-268019-b [12, 13]. 
Details are provided in Section 10.6. AESIs can be serious or non-serious. All AESIs will 
be recorded in the eCRF. Serious AESIs will be recorded and reported as described in 
Section 8.4.4. 
8.4.9 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs 
When a participant experiences a symptom corresponds to COVID-19-related symptoms, 
the investigator should carefully evaluate the relationship to COVID-19 as well as the 
relationship to the study intervention. Diagnosis of COVID-19 will not be recorded in the 
AE section of the eCRF unless it meets the criteria for an SAE.  
All events that meet the definition of an SAE will be reported as an SAE according to the 
standard process for expedited reporting of SAEs.  
8.4.10 
Special Situations - Abuse, Misuse, Overdose, and Medication 
Error  
Abuse, misuse, overdose, or medication error of the study drug (Special Situations, as 
defined below) must be reported to the sponsor (OR sponsor's medical monitor) via e-
mail by the investigator using a Special Situations Report Form (paper form) as soon as 
possible. If there are associated SAEs, the investigator must also complete and submit an 
SAE submission in EDC or using the paper SAE form as well. 
 Abuse - Persistent or sporadic, intentional excessive use of a study drug(s), which 
is accompanied by harmful physical or psychological effects. 
 Misuse - Intentional and inappropriate use of a study drug(s) other than as 
directed or indicated at any dose. 
 Overdose - Intentional or unintentional intake of study drug(s) in excess of the 
assigned dose in the protocol.  
 Medication Error - Any unintended error in the prescribing, dispensing or 
administration of a study drug(s) (including intercepted error). 
 

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8.5 
Treatment of Overdose 
In this study, any dose of study intervention greater than the doses specified in the 
protocol and doses more than 4 in total will be considered an overdose. 
sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
1. Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
2. Contact the medical monitor immediately. 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
Special Situations Report Form. 
Decisions regarding interruptions of vaccination will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
8.6 
Pharmacokinetics 
PK parameters are not evaluated in this study. 
8.7 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.8 
Genetics (Virus Genome Sequencing) 
Genetic variants of a virus arise as a natural by-product of viral replication. Some genetic 
variants of SARS-CoV-2 have been reported to date (such as 20I/501Y.V1, 
20H/501Y.V2, 20J/501Y.V3). In general, variants that confer a competitive advantage 
with respect to viral replication, transmission, or escape from immunity will increase in 
frequency. Since S-protein is a major target of COVID-19 vaccines, it becomes the focus 
of public interest whether or not mutations in the S-protein compromise vaccine 
effectiveness. In this study, nasopharyngeal swab samples will be collected at the 
Potential COVID-19 Illness Visit (SoA, Table 1-4). Nucleotide sequences of SARS-CoV-
2 strains isolated from participants diagnosed with COVID-19 will be analyzed to explore 
potential relationship between types of variants and efficacy of the investigational 
vaccine. 
Virus RNA will be extracted from nasopharyngeal swab samples collected from 
participants at (Potential) COVID-19 Illness Visit, and nucleotide sequences will be 
analyzed using the next-generation sequencing technology at the central laboratory. 
Detailed procedures for sample collection, processing, and shipping to the central 
laboratory will be specified in the Laboratory Manual. The remaining samples will be 
disposed in accordance with guidance of the central laboratories. 
8.9 
Biomarkers 
Biomarkers are not evaluated in this study. 

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8.10 Immunogenicity Assessments 
Anti-SARS-CoV-2 N-protein antibodies 
Blood samples will be collected from all participants at the time points shown in Table 
1-3. Blood samples will be shipped to the central laboratory for the immunogenicity 
assessments. These samples will be analyzed for all participants. 
Anti-SARS-CoV-2 S-protein IgG antibodies and SARS-CoV-2 neutralizing 
antibodies 
Blood samples will be collected from at least 650 participants at the time points described 
in Table 1-3 and participants who are suspected/confirmed to have COVID-19 at the time 
points described in Table 1-4. Blood samples will be shipped to the central laboratory for 
the immunogenicity assessment.  
 
Collection, processing, and shipment of the samples are described in the Laboratory 
Manual. The total blood sampling volume per participant will be approximately 36 mL.  
The assays will be performed using validated assay methods (Table 8-3). The details of 
the analyses will be provided in a separate document. 
Table 8-3 
Immunogenicity Assessments 
Analytes 
Method 
Anti-SARS-CoV-2 S-protein IgG 
antibodies 
Chemiluminescence immunoassay [CISA] 
Anti-SARS-CoV-2 N-protein antibodies 
Chemiluminescence immunoassay 
[CLIA]  
SARS-CoV-2 neutralizing antibodies 
Live virus neutralization assays 
 
Antibody titers before and after vaccination will be determined and geometric mean titer 
(GMT), geometric mean of fold rise of antibody titer (GMFR), and seroconversion rate 
will be calculated. 
8.11 Health Economics OR Medical Resource Utilization and Health 
Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 

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9. STATISTICAL CONSIDERATIONS  
9.1 
Statistical Hypotheses 
The primary efficacy endpoint is a binary response, whereby a participant is defined as a 
COVID-19 case if their first case of SARS-CoV-2 RT-PCR-positive symptomatic 
COVID-19 occurring during six months from 14 days post second vaccination in the 
Initial Vaccination Period. Otherwise, a participant is not defined as a COVID-19 case as 
the primary efficacy endpoint. Vaccine Efficacy (VE) will be calculated as 1-relative risk, 
which is the incidence of infection in the S-268019-b-preceding group (S-268019-b) 
relative to the incidence of infection in the placebo-preceding group (placebo). The null 
hypothesis is that VE is less than or equal to 30%; whereas, the alternative hypothesis is 
that VE is above 30%. That is: 
null hypothesis: VE ≤ 30% vs; alternative hypothesis: VE > 30% 
9.2 
Sample Size Determination  
Approximately 54,915 participants will be randomized in a 2:1 ratio to 2 IM doses of 
either S-268019-b (the S-268019-b-preceding group, n = approximately 36,610) or saline 
placebo (the placebo-preceding group, n = approximately 18,305) 4 weeks apart, on Days 
1 and 29. 
For the primary efficacy analysis, a total of 66 participants meeting the primary efficacy 
endpoint definition within the population of participants who are seronegative and PCR-
negative at baseline and have not met the criteria for the primary efficacy endpoint prior 
to 14 days post second vaccination are required to demonstrate with at least 90% power 
that a VE is above 30%, assuming a VE of 70%, with unblinded interim analyses for 
early efficacy stopping at 50% and 75% of the target total number of participants meeting 
the primary efficacy endpoint definition using an exact conditional test based on Poisson 
assumption with a 1-sided alpha level of 0.025 [14]. Approximately 54,915 participants 
will be randomized assuming an observed attack rate of 0.5% per year in participants 
receiving placebo, 10% of the unevaluable participants due to dropout and/or baseline 
seropositive, and 6-month follow-up of each participants. 
9.3 
Populations for Analyses 
The following analysis populations will be defined and analyzed for this study based on 
enrolled participants with Good Clinical Practice (GCP) compliance. 
Population 
Description 
Enrolled 
All participants who sign the ICF. 
Randomized 
All participants randomly assigned to study intervention. 
Full Analysis Set (FAS) 
This population will include all randomized participants who receive at 
least one dose of the study intervention in the Initial Vaccination 
Period. Participants in this population will be analyzed according to 
the treatment to which they were randomized. 

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Population 
Description 
Modified Intent to Treat 
(mITT) Population 
This population will include participants in the FAS excluding 
participants who have evidence of past or present SARS-CoV-2 
infection at baseline (ie, positive for RT-PCR or IgG antibody against 
SARS-CoV-2 N-protein). Participants in this population will be 
analyzed according to the treatment to which they were randomized. 
Per Protocol Set (PPS) 
This population will include all randomized participants who are 
included in the mITT Population and have no major protocol 
deviations in the Initial Vaccination Period. 
Crossover Subset 
This population will include all randomized participants who are 
included in the mITT Population and receive at least one dose of the 
study intervention after crossover excluding participants who have met 
the criteria for the primary efficacy endpoint in the Initial Vaccination 
Period. Participants in this population will be analyzed according to 
the treatment to which they were randomized. 
Immunogenicity Subset 
This population will include the participants selected from all 
randomized participants who are included in the mITT Population and 
have a valid immunogenicity test result prior to the first dose of 
vaccination and at least 1 valid result after the first dose of vaccination. 
Safety Analysis Set 
This population will include randomized participants who received at 
least one dose of study intervention. Participants in this population will 
be analyzed according to the intervention that they actually received. 
 
9.4 
Statistical Analyses 
The statistical analysis plan will be fixed prior to unblinding and it will include a more 
technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
9.4.1 
General Considerations 
In principle, quantitative variables will be summarized using the number of non-missing 
participants, arithmetic mean, standard deviation (SD), median, minimum, and maximum 
as summary statistics. Categorical variables will be summarized using frequency and 
percentage of participants in each category as summary statistics. 
Unless otherwise noted, all statistical tests will be performed at the two-sided significance 
level of 0.05. 
9.4.2 
Disposition of Participants 
The number and percentage of participants who complete the study and prematurely 
discontinue the study will be summarized by intervention group and by intervention 
period. Reason for study discontinuation will also be summarized by intervention group. 
The number and percentage of participants in each analysis set will be presented by 
intervention group. 

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9.4.3 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by intervention group 
using summary statistics for the Safety Analysis Set and mITT population. 
9.4.4 
Intervention Compliance 
Intervention compliance will be summarized by intervention group and by intervention 
period using summary statistics for the Safety Analysis Set. 
9.4.5 
Concomitant Medications and Therapies 
Concomitant medications will be coded using World Health Organization Drug 
Dictionary (WHODD). For the Safety Analysis Set, participants who received 
concomitant medications or therapies will be summarized by intervention group and by 
intervention period. 
9.4.6 
Efficacy Endpoint 
The primary efficacy analysis and analyses for (key) secondary efficacy endpoints will be 
performed based on the data generated in the Initial Vaccination Period. The analysis of 
data generated in the Crossover Vaccination Period will be performed using the approach 
described by Follmann et al [15]. 
9.4.6.1 
Primary Efficacy Endpoint 
The primary endpoint will be the first occurrence of SARS-CoV-2 RT-PCR-positive 
symptomatic COVID-19 in the Initial Vaccination Period (ie, prior to crossover), with 
onset at least 14 days following the second vaccination in participants seronegative and 
PCR-negative at baseline. 
9.4.6.2 
Key Secondary Efficacy Endpoint 
The key secondary endpoints are: 
 
The first occurrence of SARS-CoV-2 RT-PCR-positive severe COVID-19 in the 
Initial Vaccination Period with onset at least 14 days following the second 
vaccination in participants seronegative and PCR-negative at baseline.  
 
The first occurrence of SARS-CoV-2 RT-PCR-positive symptomatic COVID-19 in 
the Initial Vaccination Period in participants seronegative and PCR-negative at 
baseline. 
 
The first occurrence of SARS-CoV-2 RT-PCR-positive severe COVID-19 in the 
Initial Vaccination Period in participants seronegative and PCR-negative at baseline. 
9.4.6.3 
Secondary Efficacy and Immunogenicity Endpoint 
The secondary endpoints are: 

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 
The first occurrence of SARS-CoV-2 RT-PCR-positive symptomatic COVID-19 in 
the Initial Vaccination Period with onset at least 14 days following the second 
vaccination in participants regardless of serostatus or PCR status at baseline.  
 
The first occurrence of SARS-CoV-2 RT-PCR-positive severe COVID-19 in the 
Initial Vaccination Period with onset at least 14 days following the second 
vaccination in participants regardless of serostatus or PCR status at baseline.  
 
The first occurrence of SARS-CoV-2 RT-PCR-positive symptomatic COVID-19 in 
the Initial Vaccination Period in participants regardless of serostatus or PCR status at 
baseline. 
 
The first occurrence of SARS-CoV-2 RT-PCR-positive severe COVID-19 in the 
Initial Vaccination Period in participants regardless of serostatus or PCR status at 
baseline. 
 
The first occurrence of asymptomatic SARS-CoV-2 infection in the Initial 
Vaccination Period beginning 14 days following the second vaccination in 
participants seronegative and PCR-negative at baseline. Antibodies to SARS-CoV-2 
N-protein will be used to determine natural infection and to determine the incidence 
of asymptomatic infection acquired during study follow-up. 
 
The following items for SARS-CoV-2 neutralizing antibody titer and anti-SARS-
CoV-2 S-protein immunoglobulin G (IgG) antibody titers from Immunogenicity 
subset: 
- Geometric mean titer (GMT) 
- Geometric mean of fold rise of antibody titer (GMFR) 
- Seroconversion rate 
9.4.6.4 
Exploratory Efficacy and Immunogenicity Endpoint 
The exploratory endpoints are: 
 
The first occurrence of SARS-CoV-2 RT-PCR-positive symptomatic COVID-19 in 
the Crossover Vaccination Period. 
 
The first occurrence of asymptomatic SARS-CoV-2 infection in the Crossover 
Vaccination Period. Antibodies to SARS-CoV-2 N-protein will be used to determine 
natural infection and to determine the incidence of asymptomatic infection acquired 
during study follow-up. 
 
Nucleotide sequences of SARS-CoV-2 viral genomes detected in nasopharyngeal 
swabs from RT-PCR-positive participants analyzed with next-generation sequencing. 
9.4.7 
Analysis of Primary Endpoint 
The primary endpoint will be analyzed on the mITT Population and supported by analysis 
of the FAS and the PPS. 

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As the primary efficacy analysis, the plan is to use a Poisson regression model with 
robust variance to analyze the primary endpoint, which will include age as a baseline 
covariate as well as the log of the follow-up time as an offset [16]. The VE will be 
estimated from the model, which will give the relative risk in the incidence of SARS-
CoV-2 RT-PCR-positive symptomatic COVID-19 occurring during approximate six 
months (ie, from 14 days post second vaccination in the Initial Vaccination Period to the 
third vaccination in the Crossover Vaccination Period). VE is calculated as 1 minus the 
relative risk of the primary endpoint among the S-268019-b-preceding group 
(S-268019-b) versus the placebo-preceding group (placebo). The interim analysis will be 
carried out when approximately 50% (33 cases) and 75% (50 cases) of the total amount 
of statistical information is available. If the Poisson regression model with robust 
variance fails to converge, an alternative approach will be implemented. 
Supplemental analysis using the same method as the primary efficacy analysis on the 
mITT Population will be conducted in the FAS and the PPS. In addition, cumulative 
incidence rates of SARS-CoV-2 RT-PCR-positive symptomatic COVID-19 occurring in 
the Initial Vaccination Period will be estimated with the Kaplan-Meier method. 
9.4.8 
Analysis of Secondary Endpoint(s)  
The (key) secondary efficacy endpoints will be analyzed using the same manner as the 
primary efficacy analysis. 
The secondary immunogenicity endpoints will be analyzed using the Immunogenicity 
Subset. For the serum levels for SARS-CoV-2 neutralizing antibody and anti-spike 
protein IgG antibody, the GMT at each study visit, and the GMFR comparing to the 
baseline at each post-vaccination study visit, along with 95% confidence interval (CI) 
will be summarized by intervention group. The 95% CI will be calculated based on the t 
distribution of the log-transformed values for GMT or GMFR, then back transformed to 
the original scale for presentation. For SARS-CoV-2 neutralizing antibody and anti-S-
protein IgG antibody seroconversion at each post-vaccination study visit, seroconversion 
rate, along with 95% CI will be estimated for each intervention group. The 95% CI will 
be calculated using the Clopper-Pearson method. Seroconversion rate is defined as the 
percentage of participants with a ≥4-fold increase in post-vaccination antibody titer from 
baseline. 
9.4.9 
Analysis of Exploratory Endpoint(s) 
The analysis for exploratory efficacy endpoints generated in the Crossover Vaccination 
Period will be performed using the approach described by Follmann et al [15]. 
9.4.10 
Safety Analyses 
9.4.10.1 
Reactogenicity 
Reactogenicity will be measured with solicited local AEs (pain, erythema/redness, 
induration and swelling) and systemic AEs (fever, nausea/vomiting, diarrhea, headache, 
fatigue and myalgia) collected in the eCRF. The number and percentage of participants 
who had solicited local AEs and systemic AEs within 7 days after the first and second 

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vaccinations will be summarized by intervention group. These events will be tabulated by 
type of reactions, severity grade and onset. 
All safety analyses will be performed on the Safety Analysis Set. 
9.4.10.2 
Adverse Events 
Adverse Events will be classified by System Organ Class (SOC) and Preferred Term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA) developed by the 
International Council for Harmonization of Technical Requirements for Pharmaceuticals 
and Human Use (ICH). 
A treatment-emergent adverse event (TEAE) is defined as an AE occurring after the first 
dose of study intervention. Of the AE reported in the eCRF, TEAE is used for the safety 
analysis. 
The number and percentage of participants with TEAEs will be summarized by 
intervention group. 
The number of participants with at least one TEAE leading to death, other serious 
TEAEs, MAAEs, AESIs, and discontinuation of study intervention will be similarly 
summarized. Treatment-related AEs will be summarized in the same manner as TEAEs. 
Treatment-related AEs will be defined as AEs considered as “related” to the study 
intervention.  
A summary of TEAEs by MedDRA SOC and PT will be provided by intervention group 
and by intervention period, showing the number and percentage of participants with AEs. 
In addition, data will be summarized by severity, time to onset, and duration. Treatment-
related AEs will be summarized in the same manner. 
All AEs, including those occurring prior to the first dose of study intervention, will be 
listed. 
9.4.10.3 
Vital Signs 
Summary statistics for vital signs and change from baseline at each scheduled time point 
will be presented by intervention group and by intervention period. The baseline will be 
the last measurement obtained prior to study intervention (immediately prior to 
vaccination). 
9.5 
Interim Analyses 
The primary efficacy endpoint will be formally assessed by the independent data 
monitoring committee (IDMC) at 3 time points during the Initial Vaccination Period, 
giving two unblinded interim analyses and a primary analysis. The interim analyses are 
planned at 50% (33 cases) and 75% (50 cases) of the total target cases (66 cases). The 
primary objective of the interim analyses is for early detection of reliable evidence that 
VE is above 30%. The Lan-DeMets O’Brien-Fleming approximation alpha-spending 
function is used to control the overall type I error at one-sided 0.025 over the interim 

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analyses and the primary analysis. The interim analyses will be performed by an 
unblinded Biostatistics and Programming team and reviewed by the IDMC that will make 
recommendations with regard to the continuation of the trial. Regardless of the outcomes 
at either interim analysis or the final primary analysis, the study will remain blinded at 
the participant level for study site personnel and study participants until the end of the 
study. There will be an unblinded biostatistician and programmer isolated from study 
personnel. They will complete these analyses independent of study team and sponsor. A 
separate Statistical Analysis Plan will include a detailed description of the responsibilities 
of the unblinded statistician and the communication plan with the IDMC. 
9.6 
Independent Data Monitoring Committee (IDMC) 
For details on IDMC, refer to Section 10.1.5. 
 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1 
Regulatory and Ethical Considerations 
● This study will be conducted in accordance with the protocol and with the 
following: 
– Consensus ethical principles derived from international guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
– Applicable ICH Good Clinical Practice (GCP) Guidelines 
– Applicable laws and regulations 
● The protocol, protocol amendments, ICF, Investigator’s Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. Competent authority notification, review and approval may be required 
as appropriate according to local country requirements. 
● Any amendments to the protocol will require Competent authority and/or 
IRB/IEC approval (as appropriate) before implementation of changes made to the 
study design, except for changes necessary to eliminate an immediate hazard to 
study participants.  
● For studies to be submitted as part of an EU marketing authorization application 
(MAA), the sponsor will select a Clinical Study Report (CSR) Coordinating 
Investigator who will sign the CSR. 
● The investigator will be responsible for the following: 

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– Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/IEC 
– Notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures 
– Providing oversight of the conduct of the study at the site and adherence 
to requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
10.1.2 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
The information on financial disclosure for investigators will be addressed in a separate 
agreement between the sponsor and the investigator. 
10.1.3 
Informed Consent Process 
● The investigator or his/her representative must explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study.  
● Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, and Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study site.  
● The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date that written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
● Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
● A copy of the signed ICF(s) must be provided to the participant or the 
participant’s legally authorized representative.  
10.1.4 
Data Protection 
● Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information that would make the participant 
directly identifiable will not be transferred.  

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● The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent.  
● The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
● Participants’ personal data must be processed or transferred with adequate 
precautions to ensure confidentiality and compliance with applicable data privacy 
protection laws and regulations. Appropriate technical and organizational 
measures to protect the personal data against unauthorized disclosures or access, 
accidental or unlawful destruction, or accidental loss or alteration must be put in 
place.  
 
10.1.5 
Committees Structure 
Independent Data Monitoring Committee (IDMC) 
The IDMC will be established to review unblinded data, including both safety and cases 
of COVID-19 at regular intervals, at 2 planned interim analyses and at a primary analysis 
during the Initial Vaccination Period. Committee membership responsibilities, 
authorities, and procedures will be documented in the IDMC charter. 
At the interim analyses, the IDMC will review the interim analysis results and make 
recommendations based on the evaluation of the early efficacy (Section 9.5). 
All RT-PCR-positive COVID-19 cases during the study will be periodically reviewed by 
the IDMC in terms of potential vaccine-associated enhanced disease (VAED). Ad hoc 
review may be performed further to the occurrence of any vaccine-related SAE, or at 
request of the sponsor’s medical monitor or designee. The principal investigator and 
sponsor’s study responsible physician will inform the IDMC of any AE of concern. 
10.1.6 
Dissemination of Clinical Study Data 
The sponsor will disclose information on this clinical study and the summary of the study 
results when they are available on the following websites according to the regulations of 
the countries in which the study is conducted. 
Clinicaltrial.gov: http://www.clinicaltrials.gov  
EU Clinical Trials Register: https://www.clinicaltrialsregister.eu/ctr-search/search 
10.1.7 
Data Quality Assurance 
● All participant data relating to the study will be recorded on an eCRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The 

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investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the eCRF.  
● The investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF.  
● The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
● Monitoring details describing strategy (eg, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or 
on-site monitoring) are provided in the Monitoring Plan. 
● The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data.  
● The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations). 
● Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
● Before unblinding the assignment of participants to the intervention groups at the 
time of the primary immunogenicity analysis, the drug accountability records and 
the used vials should be available for verification by the unblinded sponsor 
monitor, unblinded contract research organization (CRO), or designee at each 
monitoring visit as specified in the unblinded clinical monitoring plan.  
● Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 15 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor.  
 
10.1.8 
Source Documents 
● Source documents provide evidence of the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
● Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, 
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● Source documents are defined as original documents, data, and records (eg, 
hospital records, clinical and office charts, laboratory notes, memoranda, 
participants' diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, participant files, and records kept at the 
pharmacy, laboratories, and medico-technical departments involved in the clinical 
trial). 
 
10.1.9 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
The sponsor/designee reserves the right to close the study site or terminate the study at 
any time for any reason at the sole discretion of the sponsor.  
Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected, data have been collected, 
and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
● Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
● Inadequate recruitment of participants by the investigator 
● Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow-up. 
10.1.10 
Publication Policy 
● All information regarding study intervention supplied by the sponsor to the 
investigator is privileged and confidential. The investigator agrees to use this 
information to accomplish the study and must not use it for other purposes 
without consent from the sponsor. 

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● The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
● The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
● Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 

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10.1.11 
Study Administrative Structure 
Sponsor: 
Shionogi & Co., Ltd. 
1-8, Doshomachi 3 chome, Chuo-ku, Osaka 541-0045, 
Japan 
Sponsor contact 
information: 
 
, Shionogi & Co., Ltd. 
8F, Nissay Yodoyabashi East Bldg., 3-13, Imabashi 3-
chome, Chuo-ku, Osaka 541-0042, Japan 
TEL: 
 
FAX: 
 
Sponsor’s Chief Medical 
Officer: 
 
Shionogi & Co., Ltd. 
Medical Monitor: 
 
 Shionogi & Co., Ltd. 
Emergency contact: 
 
 Shionogi & Co., Ltd. 
TEL: 
 
FAX: 
 
 
 
 Shionogi & Co., Ltd. 
TEL: 
 
FAX: 
 
IWRS: 
 
 
 
Contract Research 
Organization: 
 
 
 
Laboratory for SARS-
CoV-2 neutralizing 
antibody titer assay: 
BML, Inc. 
1-18-8, Koenji-minami, Suginami-ku, Tokyo 166-0003, 
Japan 
Laboratory for virology 
test and anti-spike protein 
IgG antibody titer test: 
LSI Medience Corporation 
1-13-4, Uchikanda, Chiyoda-ku, Tokyo 101-8517, Japan 

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10.2 Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.2.1 
Definition of AE 
AE Definition 
 
An AE is any untoward medical occurrence in a participant or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related to the 
study intervention. 
 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of study intervention. 
 
Events Meeting the AE Definition  
 
Any abnormal laboratory test results (hematology, blood chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgment of the 
investigator (ie, not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study intervention administration even though they 
may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as 
an AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as an AE or 
SAE if they fulfil the definition of an AE or SAE.  
 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
an AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of efficacy” or "failure of 
expected pharmacological action" also constitutes an AE or SAE. 
 
Events NOT Meeting the AE Definition  
 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition. 
 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s condition. 
 
Hospitalization for preplanned and elective procedures to treat a pre-existing condition that did 
not worsen after start of study will not be considered an AE, and therefore will not be considered 
an SAE despite requiring hospitalization. The exception is when the participant experiences 
another event which is fatal, is life-threatening, results in disability, leads to prolonged 
hospitalization or is considered to be medically significant during/following the procedure. 
 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 

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 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen. 
 
10.2.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the participant was 
at risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred 
or was necessary, the AE should be considered serious. 
 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline 
is not considered an AE. 
d. 
Results in persistent disability/incapacity 
 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, 
sprained ankle), which may interfere with or prevent everyday life functions but do not constitute 
a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 

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10.2.3 
Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant AE/SAE information in the eCRF. 
 
It is not acceptable for the investigator to send photocopies of the participant’s medical records to 
sponsor in lieu of completion of the AE/SAE eCRF page. 
 
There may be instances when copies of medical records for certain cases are requested by 
sponsor. In this case, all participant identifiers, with the exception of the participant number, will 
be redacted on the copies of the medical records before submission to sponsor. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator or subinvestigator will assess the intensity of solicited AEs reported during the study 
by referring to the FDA guidance [11] (see Section 10.4). However, if the participant died due to a 
solicited AE, this event will be of Grade 5 severity. 
The intensity of each non-solicited AE and SAE will be assessed and classified into one of the 
following 5 categories: 
Grade refers to the intensity of the AE. CTCAE Version 5.0 defines Grade 1 to 5 according to the 
following principles and describes the intensity of each AE individually: 
 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*. 
 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
 
Grade 5: Death related to AE. 
A semicolon (;) indicates "or" within the description of grade. 
Activities of Daily Living (ADL) 
* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. 
 
The relationship of an event to the study drug will be determined by the investigator or 
subinvestigator according to the following criteria: 
 Related: 
An AE which can be reasonably explained as having been caused   
 
by the study drug. For example, the occurrence of the AE can be  
 
 
explained by any of the following: a pharmacological effect of the   
 
study drug (eg, a similar event had been reported previously); an 
 
increase/decrease of the dose affects the occurrence or seriousness   
 
of the AE; or all other causative factors (eg, medical history,  

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concomitant medication etc.) can be ruled out after careful analysis   
 
of sufficient information. 
 Not related: An AE which cannot be reasonably explained as having been caused by the study 
drug. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment. 
 
The investigator should provide rationale for the causality assessment in the Medical Comment 
field in EDC or if reporting via paper, the rationale for causality should be provided in the 
narrative section of paper SAE form. 
 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor or CRO. However, it is very important 
that the investigator always makes an assessment of causality for every event before the 
initial transmission of the SAE data to the sponsor or CRO. 
 
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
 
Follow-up of AEs and SAEs 
 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the sponsor to elucidate the nature 
and/or causality of the AE or SAE as fully as possible. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other health care 
professionals. 
 
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor or CRO with a copy of any postmortem findings including 
histopathology.  
 
New or updated information will be recorded in the originally completed eCRF. 
 
The investigator will report any updated SAE data to the sponsor or CRO within 24 hours of 
receipt of the information. 
 
10.2.4 
Reporting of SAEs 
All SAEs must be reported to the sponsor or CRO in detail via EDC within 24 hours from 
the time point when the investigator first becomes aware of the SAE.  
SAE Reporting to sponsor via an Electronic Data Collection Tool 
 
The primary mechanism for reporting an SAE to sponsor will be EDC. 
 
If EDC is unavailable, then the site will use the paper SAE Form (see next section) in order to 
report the event within 24 hours. 
 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
 
After the study is completed at a given site, the EDC will be taken off-line to prevent the entry of 
new data or changes to existing data. 

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 
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after EDC has been taken off-line, then the site can report this 
information on a paper SAE form (see next section) or to the sponsor by telephone. 
 
Contacts for SAE reporting are indicated below. 
 
SAE Reporting to sponsor via Paper Form 
 
If EDC is unavailable, then the site will use the paper SAE Form in order to report the event 
within 24 hours. 
 
E-mail transmission is the preferred method to transmit this information to the sponsor. 
 
The investigator will complete the paper SAE Form, date, sign, and scan the Form to PDF file. 
 
The PDF file will be sent to safetyinfo@shionogi.co.jp. 
 

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10.3 Appendix 3: Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions: 
 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
● Documented hysterectomy 
● Documented tubal ligation 
● Documented bilateral salpingectomy 
● Documented bilateral oophorectomy 
 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (eg, mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
● A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
– A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation 
with more than a single FSH measurement is required.  
● Females on HRT and whose menopausal status is in doubt will be required to use 
one of the nonestrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
 

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Contraception Guidance: 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency  
● Implantable progestogen-only hormone contraception associated with inhibition 
of ovulationc 
● Intrauterine device (IUD) 
● Intrauterine hormone-releasing system (IUS) c 
● Bilateral tubal occlusion 
● Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and 
the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. Spermatogenesis cycle is 
approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the 
site personnel’s review of the participant’s medical records, medical 
examination, or medical history interview. 
Highly Effective Methodsb That Are User Dependent 
● Combined (estrogen- and progestogen-containing ) hormonal contraception 
associated with inhibition of ovulationc 
– oral 
– intravaginal 
– transdermal 
– injectable 
● Progestogen-only hormone contraception associated with inhibition of 
ovulationc 
– oral 
– injectable 
● Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk 
associated with the study intervention. The reliability of sexual abstinence needs 
to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant. 
Effective Methodsd That Are Not Considered Highly Effective Failure rate of ≥ 1% 
per year when used consistently and correctly. 
● Progestogen-only oral hormonal contraception where inhibition of ovulation is 
not the primary mode of action 
● Male or female condom with or without spermicidee 
● Cervical cap, diaphragm, or sponge with spermicide 

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● A combination of male condom with either cervical cap, diaphragm, or sponge 
with spermicide (double-barrier methods)c 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ 
from those when used consistently and correctly. 
c Male condoms must be used in addition to hormonal contraception. If locally required, in accordance 
with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are 
limited to those which inhibit ovulation as the primary mode of action. 
d Considered effective, but not highly effective - failure rate of ≥ 1% per year.  
e Male condom and female condom should not be used together (due to risk of failure from friction). 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of 
contraception.  
 
 

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Collection of Pregnancy Information 
Male Participants whose partners become pregnant 
● If the investigator recognizes that a female partner of any male participants 
becomes pregnant from the first dose of study intervention through at least 90 
days after the last dose of study intervention, the investigator will collect 
pregnancy information on the female partner. 
● After obtaining the required written consent directly from the pregnant female 
partner of the male participant, the investigator will record pregnancy information 
on the appropriate form and report it to the sponsor within 24 hours of learning of 
the participant's partner's pregnancy. The female partner of the male participant 
will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on the mother and the neonate, and the information 
will be forwarded to the sponsor. General, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Female Participants who become pregnant  
● The investigator will collect pregnancy information on any female participant 
who becomes pregnant from the first dose of study intervention through at least 
90 days after the last dose of study intervention. The initial information will be 
recorded on the appropriate form and reported to the sponsor within 24 hours of 
learning of a participant's pregnancy.  
● The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, 
and the information will be forwarded to the sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. 
Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for the procedure. 
● While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
● A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age) is always considered to be an SAE and 
will be reported as such.  
● Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.4.4. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.  
● Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention or be withdrawn from the study. 
 
 

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10.4 Appendix 4: Grading of Solicited Local and Systemic Adverse 
Events 
US FDA guidance: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials [11] 
Solicited Local AEs
 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life-
threatening 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic pain 
reliever 
> 24 hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema 
/Redness* 
2.5–5 cm 
5.1–10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration 
/Swelling** 
2.5–5 cm and does 
not interfere with 
activity 
5.1–10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
* 
In addition to grading the measured local reaction at the greatest single diameter, the measurement 
should be recorded as a continuous variable.  
**  Induration/Swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
 

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Solicited Systemic AEs
 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Potentially Life-
threatening 
(Grade 4) 
Fever 
(Oral) * 
(°C) 
(°F)   
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 – 104 
> 40 
> 104 
Fever 
(Axillary) 
(°C) 
(°F) 
37.5 – 37.9 
99.5 – 100.3 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 39.5 
101.2 – 103 
> 39.5 
> 103 
Nausea 
/vomiting 
No interference 
with activity or 
1–2 episodes/24 
hours 
Some interference 
with activity or > 2 
episodes/24 hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
2–3 loose stools 
or < 400 grams 
/24 hours 
4–5 stools or 400 – 
800 grams /24 
hours 
6 or more watery 
stools or > 800 
grams /24 hours or 
requires outpatient 
IV hydration 
ER visit or 
hospitalization 
Headache 
No interference 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or some 
interference with 
activity 
Significant; any use 
of narcotic pain 
reliever or prevents 
daily activity 
ER visit or 
hospitalization 
Fatigue 
No interference 
with activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
No interference 
with activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
* 
No recent hot or cold beverages or smoking.  
 
 

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10.5 Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments 
Phase 3-4 liver chemistry stopping criteria are designed to assure participant safety and to 
evaluate liver event etiology. 
Phase 3-4 Liver Chemistry Stopping Criteria and Follow-up assessments 
Liver Chemistry Stopping Criteria– Liver Stopping Event 
ALT or AST 
-absolute 
ALT or AST  8 × ULN 
ALT or AST 
Increase 
ALT or AST  5 × ULN but < 8 × ULN persists for  2 weeks 
ALT or AST  3 × ULN but < 5 × ULN persists for  4 weeks 
Bilirubina, b 
ALT or AST  3 × ULN and total bilirubin  2 × ULN (> 35% direct 
bilirubin)  
INRb 
ALT or AST  3 × ULN and international normalized ratio (INR) > 
1.5, if INR measured 
Cannot 
Monitor 
ALT or AST  5 × ULN but < 8 × ULN and cannot be monitored 
weekly for  2 weeks 
ALT or AST  3 × ULN but < 5 × ULN and cannot be monitored 
weekly for  4 weeks 
Symptomaticc ALT or AST  3 × ULN associated with symptoms (new or 
worsening) believed to be related to liver injury or hypersensitivity 
Required Actions, Monitoring and Suggested Follow up Assessments 
Actions 
Follow up Assessments 
● Immediately discontinue study 
intervention. 
● Report the event to the sponsor within 
24 hours. 
● Complete the Liver Event Form and 
complete a serious adverse event (SAE) 
data collection tool if the event also met 
the criteria for an SAE.b 
● Perform follow-up assessments as 
described in the Follow Up Assessment 
column.  
● Monitor the participant until liver 
chemistry test abnormalities resolve, 
stabilize, or return to baseline (see 
MONITORING). 
 
 
● Viral hepatitis serologyd 
● Obtain serum creatine 
phosphokinase (CPK) and lactate 
dehydrogenase (LDH) 
● Fractionate bilirubin, if total 
bilirubin  2 × ULN 
● Obtain complete blood count with 
differential to assess eosinophilia 
● Record the appearance or worsening 
of clinical symptoms of liver injury, 
or hypersensitivity, on the eCRF as 
an AE. 
● Record use of concomitant 
medications (including 
acetaminophen, herbal remedies, 
recreational drugs and other over-

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MONITORING: 
If ALT or AST  3 × ULN AND total 
bilirubin  2 × ULN or INR > 1.5: 
● Repeat liver chemistry tests (include 
ALT, AST, alkaline phosphatase, total 
bilirubin and INR) and perform liver 
event follow-up assessments within 24 
hours. 
● Monitor participant twice weekly until 
liver chemistry test abnormalities 
resolve, stabilize, or return to baseline. 
● A specialist or hepatology consultation is 
recommended. 
For all other criteria  
● Repeat liver chemistry tests (include 
ALT, AST, alkaline phosphatase, total 
bilirubin and INR) and perform liver 
chemistry follow-up assessments within 
24 to 72 hours. 
● Monitor participants weekly until liver 
chemistry abnormalities resolve, 
stabilize, or return to baseline. 
 
RESTART/RECHALLENGE 
● Do not restart/rechallenge participant 
with study intervention unless allowed 
per protocol and sponsor approval is 
granted. 
 
the-counter medications) on the 
eCRF. 
● Record alcohol use on the Liver 
Event Form. 
If ALT or AST ≥ 3 × ULN AND total 
bilirubin  2 × ULN or INR > 1.5 
obtain the following in addition to 
the assessments listed above: 
● Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins. 
● Serum acetaminophen adduct assay 
to access potential acetaminophen 
contribution to liver injury in 
participants with definite or likely 
acetaminophen use in the preceding 
week [17]. 
● Liver imaging (ultrasound, magnetic 
resonance, or computerized 
tomography) to evaluate liver 
disease; complete the Liver Event 
Form. 
● Liver biopsy may be considered and 
discussed with local specialists if 
available for instance: 
– In participants when serology 
raises the possibility of 
autoimmune hepatitis (AIH) 
– In participants when suspected 
DILI progresses or fails to 
resolve on withdrawal of study 
intervention 
– In participants with acute or 
chronic atypical presentation: 
hepatic vascular disorder, 
chronic hepatitis fibrosis, micro 
vesicular statosis. 
● If liver biopsy is conducted, then 
complete the Liver Event Form. 
a 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin on 
dipstick which is indicative of direct bilirubin elevations suggesting liver injury.  

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b 
All events of ALT or AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN (> 35% direct bilirubin) or ALT 
or AST ≥ 3 × ULN and INR > 1.5 may indicate severe liver injury and must be reported to sponsor 
in an expedited manner and as an SAE (excluding studies of hepatic impairment or cirrhosis). 
The INR stated threshold value will not apply to participants receiving anticoagulants.  
c 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or 
eosinophilia). 
d 
Includes: hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; 
cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
heterophile antibody or monospot testing); and hepatitis E IgM antibody. In those with underlying 
chronic hepatitis B at study entry (identified by positive hepatitis B surface antigen) quantitative 
hepatitis B DNA and hepatitis delta antibody. If hepatitis delta antibody assay cannot be performed, it 
can be replaced with a polymerase chain reaction (PCR) of hepatitis D RNA virus (where needed) [18]. 
 
Phase 3-4 Liver Chemistry Increased Monitoring Criteria with Continued Study 
Intervention 
Liver Chemistry Increased Monitoring Criteria and Actions with Continued 
Study Intervention 
Criteria 
Actions 
ALT or AST  5 × ULN and 
< 8 × ULN and total bilirubin 
< 2 × ULN or INR < 1.5 without 
symptoms believed to be related to 
liver injury or hypersensitivity, 
and who can be monitored weekly 
for 2 weeks. 
OR 
ALT or AST  3 × ULN and 
< 5 × ULN and total bilirubin 
< 2 × ULN without symptoms 
believed to be related to liver 
injury or hypersensitivity, and who 
can be monitored weekly for 4 
weeks. 
 
● Notify the sponsor within 24 hours of 
learning of the abnormality to discuss 
participant safety.  
● Participant can continue study intervention 
● Participant must return weekly for repeat liver 
chemistry tests (ALT, AST, alkaline 
phosphatase, total bilirubin) until the 
abnormalities resolve, stabilize, or return to 
baseline.  
● If at any time, the participant meets liver 
chemistry stopping criteria, proceed as 
described in Section 7.1. 
● If ALT or AST decreases from ALT or AST  
5 × ULN and < 8 × ULN to ≥ 3 × ULN but < 
5 × ULN, continue to monitor liver 
chemistries weekly.  
● If after 4 weeks of monitoring, ALT or AST < 
3 × ULN and total bilirubin < 2 × ULN, 
monitor participants twice monthly until liver 
chemistry tests resolve, stabilize, or return to 
baseline. 
 
 
 
 

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10.6 Appendix 6: List of AESIs 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
 
Cranial nerve neuropathy, 
including paralysis and 
paresis (eg, Bell’s palsy). 
 
Optic neuritis. 
 
Multiple sclerosis. 
 
Transverse myelitis. 
 
Guillain-Barré syndrome, 
including Miller Fisher 
syndrome and other 
variants. 
 
Acute disseminated 
encephalomyelitis, 
including site specific 
variants, eg, noninfectious 
encephalitis, 
encephalomyelitis, 
myelitis, 
myeloradiculoneuritis. 
 
Myasthenia gravis, 
including Lambert-Eaton 
myasthenic syndrome. 
 
Demyelinating peripheral 
neuropathies including: 
- 
Chronic inflammatory 
demyelinating 
polyneuropathy. 
- 
Multifocal motor 
neuropathy. 
- 
Polyneuropathies 
associated with 
monoclonal 
gammopathy. 
 
Narcolepsy. 
 
Systemic lupus 
erythematosus and 
associated conditions. 
 
Systemic scleroderma 
(systemic sclerosis), 
including: 
- 
Diffuse scleroderma. 
- 
CREST syndrome. 
 
Idiopathic inflammatory 
myopathies, including: 
- 
Dermatomyositis. 
- 
Polymyositis. 
 
Anti-synthetase 
syndrome. 
 
Rheumatoid arthritis and 
associated conditions 
including: 
- 
Juvenile idiopathic 
arthritis. 
- 
Still’s disease. 
 
Polymyalgia rheumatica. 
 
Spondyloarthropathies, 
including: 
- 
Ankylosing 
spondylitis. 
- 
Reactive arthritis 
(Reiter’s syndrome). 
- 
Undifferentiated 
spondyloarthritis. 
- 
Psoriatic arthritis. 
- 
Enteropathic arthritis. 
 
Relapsing polychondritis. 
 
Mixed connective tissue 
disorder. 
 
Gout. 
 
Psoriasis. 
 
Vitiligo. 
 
Erythema nodosum. 
 
Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid, and 
dermatitis herpetiformis). 
 
Lichen planus. 
 
Sweet’s syndrome. 
 
Localized scleroderma 
(morphea). 
Liver disorders 
Gastrointestinal disorders 
Endocrine disorders 
 
Autoimmune hepatitis. 
 
Primary biliary cirrhosis. 
 
Primary sclerosing 
cholangitis. 
 
Autoimmune cholangitis. 
 
Inflammatory bowel 
disease, including: 
- 
Crohn’s disease. 
- 
Ulcerative colitis. 
- 
Microscopic colitis. 
- 
Ulcerative proctitis. 
 
Celiac disease. 
 
Autoimmune pancreatitis. 
 
Autoimmune thyroiditis 
(Hashimoto thyroiditis). 
 
Grave’s or Basedow’s 
disease. 
 
Diabetes mellitus type 1. 
 
Addison’s disease. 
 
Polyglandular autoimmune 
syndrome. 
 
Autoimmune hypophysitis. 
Vasculitis 
Blood disorders 
Others 
 
Large vessels vasculitis 
including: 
 
Autoimmune hemolytic 
anemia. 
 
Autoimmune 
glomerulonephritis including: 
- 
IgA nephropathy. 

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- 
Giant cell arteritis 
(temporal arteritis). 
- 
Takayasu’s arteritis. 
 
Medium sized and/or small 
vessels vasculitis including: 
- 
Polyarteritis nodosa. 
- 
Kawasaki’s disease. 
- 
Microscopic 
polyangiitis. 
- 
Wegener’s 
granulomatosis 
(granulomatosis with 
polyangiitis). 
- 
Churg–Strauss 
syndrome (allergic 
granulomatous angiitis 
or eosinophilic 
granulomatosis with 
polyangiitis). 
- 
Buerger’s disease 
(thromboangiitis 
obliterans). 
- 
Necrotizing vasculitis 
(cutaneous or 
systemic). 
- 
Antineutrophil 
cytoplasmic antibody 
(ANCA) positive 
vasculitis (type 
unspecified). 
- 
Henoch-Schonlein 
purpura (IgA 
vasculitis). 
- 
Behcet’s syndrome. 
- 
Leukocytoclastic 
vasculitis. 
 
Autoimmune 
thrombocytopenia. 
 
Antiphospholipid 
syndrome. 
 
Pernicious anemia. 
 
Autoimmune aplastic 
anemia. 
 
Autoimmune neutropenia. 
 
Autoimmune 
pancytopenia. 
- 
Glomerulonephritis 
rapidly progressive. 
- 
Membranous 
glomerulonephritis. 
- 
Membranoproliferative 
glomerulonephritis. 
- 
Mesangioproliferative 
glomerulonephritis. 
- 
Tubulointerstitial 
nephritis and uveitis 
syndrome. 
 
Ocular autoimmune diseases 
including: 
- 
Autoimmune uveitis. 
- 
Autoimmune retinitis. 
 
Autoimmune myocarditis. 
 
Sarcoidosis. 
 
Stevens-Johnson syndrome. 
 
Sjögren’s syndrome. 
 
Alopecia areata. 
 
Idiopathic pulmonary 
fibrosis. 
 
Goodpasture syndrome. 
 
Raynaud’s phenomenon. 
 
 
 
 
 

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10.7 Appendix 7: Abbreviations and Acronyms 
ACE2 
angiotensin-converting enzyme 2 
AE 
adverse event 
AESI 
adverse event of special interest 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BEVS 
baculovirus expression vector system 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CLIA 
chemiluminescence enzyme immunoassay 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CPK 
creatine phosphokinase 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
diastolic blood pressure 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram/electrocardiography  
ECMO 
extracorporeal membrane oxygenation 
eCRF 
electronic case report form 
EDC 
electronic data capture system 
ELISA 
enzyme-linked immunosorbent assay 
ER 
emergency room 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
good clinical practice 
GMFR 
geometric fold rise 
GMT 
geometric mean titer 
HBsAg 
hepatitis B surface antigen 
HIPAA 
Health Information Portability and Accountability Act 

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HRT 
hormonal replacement therapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use  
ICU 
intensive care unit 
IDMC 
independent data monitoring committee 
IEC 
institutional ethics committee 
IgG 
immunoglobulin G 
IMP 
investigational medicinal product 
IRB 
institutional review board 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IWRS 
interactive web response system 
LDH 
lactate dehydrogenase 
MAAE 
medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
NAb 
neutralizing antibody 
NIMP 
non-investigational medicinal product 
N-protein 
SARS-CoV-2 nucleocapsid protein 
PCR 
polymerase chain reaction 
PPS 
per-protocol set 
RNA 
ribonucleic acid 
RT-PCR 
real-time polymerase chain reaction 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBP 
systolic blood pressure 
SD 
standard deviation 
SoA 
schedule of assessments 
SpO2 
peripheral capillary oxygen saturation 
S-protein 
SARS-CoV-2 spike protein 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal  
US 
United State of America 
VE 
vaccine efficacy 
WHO 
World Health Organization 

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WHODD 
World Health Organization Drug Dictionary 
WOCBP 
women of child-bearing potential 
 
 
 

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10.8 Appendix 8: Investigator’s Signature  
 
Study Title: 
A Phase 3, Randomized, Observer-Blind, Placebo-
Controlled Cross-over Study to Evaluate the Efficacy, 
Safety, and Immunogenicity of S-268019 for the 
Prevention of COVID-19 
Study Number: 
2126U0232 
Date of Original: 
28 Oct 2021 
Date of Latest Version: 
8 Jul 2022 
 
I have read the protocol described above. I agree to comply with all applicable 
regulations and to conduct the study as described in the protocol. 
 
Signed: 
 
 
 
 
 
 
Date:  
 
 
 
 

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11. 
REFERENCES 
1. WHO Coronavirus (COVID-19) Dashboard. https://covid19.who.int/ Accessed 7 July 
2022. 
2. Cevik M, Kuppalli K, Kindrachuk J, Peiris M. Virology, transmission, and 
pathogenesis of SARS-CoV-2. BMJ 2020;371:m3862. 
3. Benton DJ, Wrobel AG, Xu P, et al. Receptor binding and priming of the spike 
protein of SARS-CoV-2 for membrane fusion. Nature 2020;588:327-30. 
4. Bozkurt B, Kamat I, Hotez PJ. Myocarditis With COVID-19 mRNA Vaccines. 
Circulation 2021;144:471-84. 
5. Sharifian-Dorche M, Bahmanyar M, Sharifian-Dorche A, et al. Vaccine-induced 
immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis post 
COVID-19 vaccination; a systematic review. J Neurol Sci 2021;428:117607. 
6. Felberbaum RS. The baculovirus expression vector system: A commercial 
manufacturing platform for viral vaccines and gene therapy vectors. Biotechnol J 
2015;10(5):702-14. 
7. S-268019 Investigator’s Brochure  
8. Zou G. A Modified Poisson Regression Approach to Prospective Studies with Binary 
Data. Am J Epidemiol 2004; 159 (7):702-6.  
9. Guidance for Industry. Development and Licensure of Vaccines to Prevent COVID-
19. US Food and Drug Administration. June 2020. 
10. CDC. (Centers for Disease Control and Prevention). Coronavirus Disease 2019 
(COVID-19), Symptoms of Coronavirus. https://www.cdc.gov/coronavirus/2019-
ncov/symptomstesting/symptoms.html. Published 2020. 
11. Guidance for Industry. Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials. US Food and Drug 
Administration. September 2007. 
12. Goepfert PA, Fu B, Chabanon A-L, et al. Safety and immunogenicity of SARS-CoV-
2 recombinant protein vaccine formulations in healthy adults: interim results of a 
randomised, placebo-controlled, phase 1–2, dose-ranging study. Lancet Infect Dis 
2021, Published online, April 19, 2021. 
13. Tavares Da Silva F, De Keyser F, Lambert PH, et al. Optimal approaches to data 
collection and analysis of potential immune mediated disorders in clinical trials of 
new vaccines. Vaccine 2013;31:1870-6. 
14. Chan ISF, Bohidar NR. Exact power and sample size for vaccine efficacy studies. 
Commun Statist-Theory Meth 1998: 27(6); 1305-22. 
15. Follmann D, Fintzai J, Fay MP, et al. Assessing Durability of Vaccine Effect 
Following Blinded Crossover in COVID-19 Vaccine Efficacy Trials. medRxiv 2020 
Dec 14 Preprint. 

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Clinical Study Protocol: 2126U0232 
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Page 82 of 82 
16. Zou G. A Modified Poisson Regression Approach to Prospective Studies with Binary 
Data. Am J Epidemiol 2004; 159 (7):702-6.  
17. James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of Acetaminophen-Adduct 
in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab 
Dispos 2009; 37:1779-84. 
18. Le Gal F, Gordien E, Affolabi D, et al. Quantification of Hepatitis Delta Virus RNA 
in Serum by Consensus Real-Time PCR Indicates Different Patterns of Virological 
Response to Interferon Therapy in Chronically Infected Patients. J Clin Microbiol 
2005;43(5):2363-9. 

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