A Phase 1/2 Randomized, Observer-Blind Study of the Safety, Reactogenicity, and Immunogenicity of 3 SARS-CoV-2 RNA Vaccine Candidates in Adults Previously Vaccinated and Not Previously Vaccinated Against SARS-CoV-2
Phase: PHASE1
Conditions: COVID-19, SARS-CoV-2 Infection, Corona Virus Infection
Sponsor: Arcturus Therapeutics, Inc.

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CLINICAL STUDY PROTOCOL 
A Phase 1/2 Randomized, Observer-Blind Study of the Safety, Reactogenicity, 
and Immunogenicity of 3 SARS-CoV-2 RNA Vaccine Candidates in Adults 
Previously Vaccinated and Not Previously Vaccinated Against SARS-CoV-2 
PROTOCOL NO. ARCT-165-01 
Sponsor: 
Arcturus Therapeutics, Inc. 
10628 Science Center Dr #250 
San Diego, CA 92121 
Version of Protocol: 
4.0 
Date of Protocol:  
22 August 2022 
Previous Versions: 
3.0 
Compound Name: 
ARCT-021, ARCT-154, and ARCT-165 
Study Phase: 
1/2 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6(R2): Good Clinical Practice 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Arcturus Therapeutics, Inc. This document 
contains information that is confidential, proprietary, and/or under the control of Arcturus Therapeutics, Inc. The 
information is only to be used in connection with authorized clinical studies of the investigational drug described in 
the protocol provided herewith. You may disclose the contents of this document while acting in the capacity of an 
Investigator, potential Investigator, or consultant to study personnel under your supervision and/or to an applicable 
Institutional Review Board or Independent Ethics Committee who need to know the contents for the aforementioned 
purpose and who have been advised of the confidential nature of the document. You may not disclose any of the 
information to others without written authorization from Arcturus Therapeutics, Inc. except to the extent necessary 
to obtain informed consent from those persons to whom the drug may be administered. 
NCT #: NCT05037097

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Protocol ARCT-165-01, Version 4.0 
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PROTOCOL APPROVAL – SPONSOR SIGNATORY 
 
Study Title 
A Phase 1/2 Randomized, Observer-Blind Study of the Safety, 
Reactogenicity, and Immunogenicity of 3 SARS-CoV-2 RNA Vaccine 
Candidates in Adults Previously Vaccinated and Not Previously 
Vaccinated Against SARS-CoV-2 
Protocol Number 
ARCT-165-01 
Protocol Date 
and Version 
22 August 2022 (Version 4.0) 
 
Protocol accepted and approved by: 
 Clinical Development, Vaccines 
 
Arcturus Therapeutics, Inc. 
10628 Science Center Dr #250 
San Diego, CA 92121 
 
 
 
Signature 
 
Date 

Arcturus Therapeutics, Inc. 
 
Protocol ARCT-165-01, Version 4.0 
22 August 2022 
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DECLARATION OF INVESTIGATOR 
I have read and understood all sections of the protocol titled “A Phase 1/2 Randomized, 
Observer-Blind Study of the Safety, Reactogenicity, and Immunogenicity of 
3 SARS-CoV-2 RNA Vaccine Candidates in Adults Previously Vaccinated and Not 
Previously Vaccinated Against SARS-CoV-2” and the accompanying Investigator’s Brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with ethical principles that have their origin in the Declaration of Helsinki, the 
International Council for Harmonisation harmonised tripartite guideline E6(R2): Good Clinical 
Practice, the Protocol Version 4.0, dated 22 August 2022, and all applicable government 
regulations. I will not make changes to the protocol before consulting with Arcturus 
Therapeutics, Inc. or implement protocol changes without independent ethics committee 
approval except to eliminate an immediate risk to participants. I agree to administer study 
treatment only to participants under my personal supervision or the supervision of a 
sub-Investigator. 
I will not supply the study vaccine to any person not authorized to receive it. Confidentiality will 
be protected. Participant identity will not be disclosed to third parties or appear in any study 
reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Arcturus Therapeutics, Inc. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 

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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ................................................................................................ 1 
PROTOCOL APPROVAL – SPONSOR SIGNATORY .............................................................. 2 
DECLARATION OF INVESTIGATOR ....................................................................................... 3 
TABLE OF CONTENTS ............................................................................................................... 4 
LIST OF TABLES ......................................................................................................................... 8 
LIST OF FIGURES ....................................................................................................................... 9 
LIST OF APPENDICES ................................................................................................................ 9 
PROTOCOL SYNOPSIS............................................................................................................. 10 
LIST OF ABBREVIATIONS ...................................................................................................... 15 
1 
INTRODUCTION ........................................................................................................... 18 
1.1 
Background ................................................................................................................... 18 
1.2 
Current Therapies for COVID-19 ................................................................................. 18 
1.3 
Therapeutic Rationale for ARCT-165 and ARCT-154 in Prevention of COVID-
19 .................................................................................................................................. 19 
1.4 
Mechanism of Action .................................................................................................... 20 
1.5 
Clinical Study Experience with ARCT-165, ARCT-154, and ARCT-021 ................... 21 
1.6 
Rationale for Dose Regimen Selection ......................................................................... 22 
1.7 
Risk Benefit Assessment ............................................................................................... 23 
1.7.1 
Potential Risks ........................................................................................................... 23 
1.7.2 
Potential Benefits ....................................................................................................... 25 
1.7.3 
Overall Risk: Benefit Assessment ............................................................................. 26 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................... 27 
2.1 
Primary Objectives and Endpoints ................................................................................ 27 
2.2 
Exploratory Objectives and Endpoints ......................................................................... 28 
3 
INVESTIGATIONAL PLAN .......................................................................................... 30 
3.1 
Study Design ................................................................................................................. 30 
3.1.1 
Rationale for Study Design ........................................................................................ 31 
4 
PARTICIPANT SELECTION AND WITHDRAWAL CRITERIA ............................... 33 
4.1 
Selection of Study Participants ..................................................................................... 33 

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4.1.1 
Inclusion Criteria ....................................................................................................... 33 
4.1.2 
Exclusion Criteria ...................................................................................................... 34 
4.1.3 
Screen Failures ........................................................................................................... 36 
4.2 
Delaying or Discontinuing Study Treatment and Participant Withdrawal From 
the Study ....................................................................................................................... 36 
4.2.1 
Delay in Study Treatment .......................................................................................... 36 
4.2.2 
Discontinuation of Study Vaccine (Participant) ........................................................ 37 
4.2.2.1 
Stopping Rules for Adverse Events in Individual Participants ............................... 37 
4.2.2.2 
Stopping Rules in Individual Participants for Other Circumstances ...................... 37 
4.2.3 
Withdrawal of Participant From Study ...................................................................... 37 
4.2.4 
Study-Wide Pausing and Stopping Rules .................................................................. 38 
4.2.5 
Lost to Follow-Up ...................................................................................................... 39 
4.2.6 
Replacements ............................................................................................................. 40 
4.3 
Discontinuation of Study .............................................................................................. 40 
5 
STUDY TREATMENTS ................................................................................................. 41 
5.1 
Method of Assigning Participants to Study Groups ..................................................... 41 
5.2 
Study Vaccine, Dosage, and Route of Administration ................................................. 41 
5.3 
Management of Clinical Supplies ................................................................................. 41 
5.3.1 
Investigational Product Packaging and Storage ......................................................... 41 
5.3.2 
Study Vaccine Accountability ................................................................................... 42 
5.3.3 
Other Supplies for Participant Use ............................................................................ 42 
5.4 
Overdose Management ................................................................................................. 42 
5.5 
Blinding......................................................................................................................... 43 
5.5.1 
Breaking the Blind ..................................................................................................... 43 
5.6 
Compliance with Study Treatment ............................................................................... 44 
5.7 
Concomitant and Rescue Therapies and Procedures .................................................... 44 
5.7.1 
Concomitant Therapy................................................................................................. 44 
5.7.2 
Prohibited Concomitant Vaccines and Concomitant Therapy ................................... 44 
5.7.3 
Concomitant Procedures ............................................................................................ 45 
5.7.4 
Rescue Medication ..................................................................................................... 45 

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5.8 
Dose Modification ........................................................................................................ 45 
5.9 
Intervention After the End of the Study ........................................................................ 45 
6 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 46 
6.1 
Study Procedures .......................................................................................................... 46 
6.1.1 
Physical Examinations ............................................................................................... 46 
6.1.2 
Vital Signs and Body Temperature ............................................................................ 46 
6.1.3 
Pregnancy Testing ...................................................................................................... 46 
6.1.4 
Safety Blood Sampling .............................................................................................. 46 
6.1.5 
Nasopharyngeal Swab Sampling ............................................................................... 46 
6.1.6 
Immunogenicity Blood Sampling .............................................................................. 47 
6.1.7 
Diary Card Procedures ............................................................................................... 47 
6.2 
Study Assessments and Visits ....................................................................................... 47 
6.2.1 
Cohort A Visits .......................................................................................................... 47 
6.2.1.1 
Screening................................................................................................................. 47 
6.2.1.2 
Vaccination Visits (Days 1 and 29) ........................................................................ 48 
6.2.1.3 
Post-vaccination Visits on Days 4, 8, 32, and 36.................................................... 48 
6.2.1.4 
Post-vaccination Visits on Days 15 and 43............................................................. 49 
6.2.1.5 
Post-vaccination Visit on Day 57 ........................................................................... 49 
6.2.1.6 
Post-vaccination Visits on Days 119, 209, and 299................................................ 49 
6.2.1.7 
Final Visit on Day 394/Early Termination Visit..................................................... 49 
6.2.2 
Cohort B Visits .......................................................................................................... 50 
6.2.2.1 
Screening................................................................................................................. 50 
6.2.2.2 
Vaccination Visit on Day 1 ..................................................................................... 50 
6.2.2.3 
Post-vaccination Visits on Days 4 and 8................................................................. 51 
6.2.2.4 
Post-vaccination Visits on Days 15, 29, 91, 181, and 271...................................... 51 
6.2.2.5 
Final Visit Day 366/Early Termination Visit .......................................................... 52 
6.2.3 
Unscheduled Visits (both Cohort A and B) ............................................................... 52 
6.3 
Safety Assessments ....................................................................................................... 52 
6.3.1 
Adverse Events .......................................................................................................... 52 
6.3.1.1 
Definitions............................................................................................................... 52 

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6.3.1.2 
Adverse Events ....................................................................................................... 52 
6.4 
Physical Examinations .................................................................................................. 59 
6.5 
Vital Signs and Body Temperature ............................................................................... 59 
6.6 
Pregnancy ...................................................................................................................... 59 
6.7 
Surveillance for SARS-CoV-2 Infection ...................................................................... 60 
7 
STATISTICAL CONSIDERATIONS............................................................................. 63 
7.1 
Sample Size Considerations .......................................................................................... 63 
7.2 
Populations .................................................................................................................... 63 
7.3 
Definition of Baseline ................................................................................................... 63 
7.4 
Interim Analysis ............................................................................................................ 63 
7.5 
Planned Methods of Analysis ....................................................................................... 64 
7.5.1 
General Approach ...................................................................................................... 64 
7.5.2 
Demographic and Baseline Characteristics ............................................................... 64 
7.5.3 
Safety Analysis .......................................................................................................... 64 
7.5.4 
Immunogenicity Analyses ......................................................................................... 65 
7.5.5 
Missing Data Handling .............................................................................................. 65 
7.6 
Monitoring Committees ................................................................................................ 65 
7.6.1 
Safety Review Committee ......................................................................................... 65 
8 
DATA QUALITY ASSURANCE ................................................................................... 66 
8.1 
Data Management ......................................................................................................... 66 
8.2 
Data Disclosure ............................................................................................................. 66 
9 
ETHICS............................................................................................................................ 67 
9.1 
Independent Ethics Committee or Institutional Review Board .................................... 67 
9.2 
Ethical Conduct of the Study ........................................................................................ 67 
9.3 
Participant Information and Consent ............................................................................ 67 
10 
INVESTIGATOR’S OBLIGATIONS ............................................................................. 69 
10.1 
Confidentiality .............................................................................................................. 69 
10.2 
Data Protection.............................................................................................................. 69 
10.3 
Financial Disclosure and Obligations ........................................................................... 70 
10.4 
Investigator Documentation .......................................................................................... 70 

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10.5 
Study Conduct ............................................................................................................... 70 
10.6 
Adverse Events and Study Report Requirements ......................................................... 70 
10.7 
Investigator’s Final Report ........................................................................................... 70 
10.8 
Records Retention ......................................................................................................... 70 
10.9 
Publications and Results Disclosures............................................................................ 71 
11 
STUDY MANAGEMENT .............................................................................................. 72 
11.1 
Monitoring .................................................................................................................... 72 
11.1.1 
Monitoring of the Study ............................................................................................. 72 
11.1.2 
Inspection of Records ................................................................................................ 72 
11.2 
Management of Protocol Amendments and Deviations ............................................... 72 
11.2.1 
Modification of the Protocol ...................................................................................... 72 
11.2.2 
Protocol Deviations .................................................................................................... 73 
11.3 
End of Study ................................................................................................................. 73 
11.4 
Early Study Termination ............................................................................................... 73 
11.5 
Final Report .................................................................................................................. 73 
12 
REFERENCES ................................................................................................................ 75 
13 
APPENDICES ................................................................................................................. 82 
 
LIST OF TABLES 
Table 1 
Risk Minimization Measures Included in Clinical Studies of ARCT-021, 
ARCT-154, and ARCT-165 ................................................................................. 23 
Table 2 
Primary Objectives and Endpoints ....................................................................... 27 
Table 3 
Exploratory Objectives and Endpoints ................................................................ 28 
 
 
 

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LIST OF FIGURES 
Figure 1 
ARCT-165-01 Study Schema .............................................................................. 31 
 
LIST OF APPENDICES 
Appendix 1 Schedule of Assessments - Cohort A (Including A1 and A2) ................................. 83 
Appendix 2 Schedule of Assessments - Cohort B ....................................................................... 87 
Appendix 3 Clinical Laboratory Tests ......................................................................................... 90 
Appendix 4 Contraceptive Guidance ........................................................................................... 92 
Appendix 5 Toxicity Grading Scale Solicited Adverse Events ................................................... 95 
Appendix 6 List of Exclusionary Autoimmune Diseases ............................................................ 97 
Appendix 7 Case Definitions for COVID-19 ............................................................................ 101 
Appendix 8 Protocol Amendments ............................................................................................ 104 
 

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PROTOCOL SYNOPSIS 
Protocol Number: ARCT-165-01 
Title 
A Phase 1/2 Randomized, Observer-Blind Study of the Safety, Reactogenicity, 
and Immunogenicity of 3 SARS-CoV-2 RNA Vaccine Candidates in Adults 
Previously Vaccinated and Not Previously Vaccinated Against SARS-CoV-2 
Phase 
1/2 
Study Design 
This is a randomized, observer-blind study evaluating the safety, reactogenicity, 
and immunogenicity of 3 investigational SARS-CoV-2 self-amplifying 
ribonucleic acid (RNA) vaccines. This study is intended for execution in one or 
more clinical study sites in one or more of the following countries – Singapore, 
South Africa and the United States (US). 
The study will initially enroll approximately 72 adult participants divided into 
2 cohorts of 36 adult participants based on previous vaccination status against 
the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).  In Cohort 
B the randomization is 1:1:1 (n= 36 participants total). Cohort A is further 
subdivided into two sub-cohorts: A1 (n = 12 participants, seronegative, not 
previously vaccinated individuals) assigned 1:1:1 to ARCT-021 vs. ARCT-154 
vs. ARCT-165 and A2 (n=24 participants, seropositive, not previously 
vaccinated individuals) assigned 3:1 ARCT-154 vs. ARCT-021 respectively. 
Based on the review of interim analysis data, the study may be amended to 
further explore LUNAR SARS-CoV-2 vaccine development. The intended 
enrollment plan for additional participants will be shared with applicable health 
authorities and ethics committee prior to initiation of enrollment.  
The first cohort (Cohort A) will include a total of 36 adult participants ≥21 to 
≤65 years of age who have not been previously vaccinated with a SARS-CoV-2 
vaccine. Study vaccine will be given as 2 doses on Days 1 and 29. 
The second cohort (Cohort B) will include a total of 36 adult participants ≥21 to 
≤65 years of age who have been previously vaccinated (5 months or longer 
prior to study enrollment) with the BNT162b2 (Comirnaty) SARS-CoV-2 
vaccine. Study vaccine will be given as a single dose on Day 1. 
The first 3 participants (sentinel participants) enrolled in Sub-cohort A1 and 
Cohort B will be randomly assigned (1:1:1) to 1 of 3 study vaccines 
(ARCT-021, ARCT-154, and ARCT-165) administered in a blinded, parallel 
dosing fashion and the first 4 participants (sentinel participants) enrolled in 
Sub-cohort A2 will be randomly assigned (3:1) to ARCT-154 or ARCT-021. 
Safety in each of these initial cohort participants (3 participants in Sub-cohort 
A1 and. Cohort B each and 4 participants in Cohort A2) will be evaluated for 
3 days after vaccination. These safety data will also be reviewed by a blinded 
Safety Review Committee (SRC) prior to the start of dosing of remaining 
participants in these cohorts.  
The study will also include the use of pausing and stopping rules that may pause 
or stop dosing of study vaccination based on any unexpected safety concerns.  
Throughout the study, participants will be regularly assessed for safety using 
solicited and unsolicited adverse event collection, concomitant medication, 
vaccination, and procedure collection, physical examinations, vital signs (VS), 
body temperature and safety laboratory assessments as specified in the Schedule 
of Assessments.  

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Participants will also undergo blood sampling for antibody and cell mediated 
immunity (CMI) responses to SARS-CoV-2 vaccines as well as for collection 
of sera for possible use in non-clinical passive transfer studies. Participants who 
develop symptoms of coronavirus disease 2019 (COVID-19) or who are 
exposed to someone who has been diagnosed with COVID-19 or SARS-CoV-2 
infection will undergo testing to determine if the participant has SARS-CoV-2 
infection. Safety, immunogenicity, and COVID-19 assessments will be 
performed through the duration of study participation as specified in the 
Schedule of Assessments. 
Rationale for Study Design 
The SARS-CoV-2 pandemic that was declared in 2020 is continuing to cause 
global COVID-19 disease in 2021 despite success in developing and emergency 
use of vaccines directed against the SARS-CoV-2 strain. Control of the disease 
is complicated by both supply constraints and the emergence of variant strains 
that may be resistant to vaccination. Additional vaccines that can address 
priming and boosting vaccination as well as coverage against variants are 
needed. 
This Phase 1/2 study is designed to evaluate the safety, reactogenicity, and 
immunogenicity of 3 investigational vaccines developed to address the 
SARS-CoV-2 virus and all developed on the same RNA manufacturing 
platform: ARCT-021 vaccine, which was developed against the original 
ancestral strain; ARCT-154 vaccine, which was developed to include the 
mutation seen in the ancestral strain-D614G variant; and ARCT-165 vaccine, 
which was developed to include the mutations seen in the SARS-CoV-2 Beta 
variant strain. These 3 investigational vaccines will be administered to 
individuals who either may or may not have been previously vaccinated against 
SARS-CoV-2. 
As these vaccines are built with the same lipid nanoparticle composition and 
very similar RNA composition to the ARCT-021 vaccine, which has been 
evaluated in 3 other clinical studies, the starting dose (5 µg) will be based on 
that previous clinical experience. ARCT-021 is a more pertinent comparator 
than placebo for the assessment of study objectives as its safety and 
immunogenicity have been well characterized; also, given the presence of 
vaccination campaigns in Singapore, South Africa, and the US, it is difficult to 
ethically withhold active vaccine from placebo participants.  The introduction 
of Sub-cohort A2 in protocol v3.0 allows for the further assessment of study 
vaccines ARCT-154 and ARCT-021 in SARS-CoV-2-vaccine-naïve 
participants who are seropositive at baseline and will provide valuable safety 
and immunogenicity data in this important population. Given the stage of the 
pandemic and high seropositivity rates worldwide amongst unvaccinated 
populations, understanding the performance of the vaccines and gaining clinical 
experience in these settings will support ongoing and further clinical 
development efforts. Preliminary data from the vaccines evaluated in Cohort B 
of this study highlight that ARCT-154 appears to have broader antibody 
responses than the ARCT-165 vaccine (Arcturus 2022b, Arcturus 2022c). For 
this exploratory study, the shift in randomization will allow for more 
characterization of the ARCT-154 vaccine immunogenicity in individuals who 
have signs of prior exposure to one or more SARS-CoV-2 strains.  ARCT-021 
will be used primarily as a comparator for safety in this randomization scheme. 
This study is expected to inform future clinical development planning for 
SARS-CoV-2 vaccine candidates ARCT-154 and ARCT-165, which are 

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intended for administration to individuals who may or may not have been 
previously vaccinated. 
Target Population 
Adult participants ≥21 to ≤65 years of age will initially be enrolled in one or 
more of the following countries – Singapore, South Africa or the US. Cohort A 
participants will not have previously received SARS-CoV-2 vaccinations while 
participants in Cohort B will have previously received 2 doses of the 
BNT162b2 SARS-CoV-2 vaccine 5 months or longer prior to study enrollment.  
Number of Participants 
Approximately 72 adults ≥21 to ≤65 years of age (up to a maximum of 
144 adults ≥21 to ≤80 years if additional cohorts are added) will be enrolled. 
Cohort A will include approximately 36 SARS-CoV-2 vaccine-naïve adults. 
Within Cohort A, Sub-cohort A1 will include 12 participants who are 
seronegative at screening and Sub-cohort A2 will include 24 participants who 
are seropositive at screening. 
Cohort B will include approximately 36 SARS-CoV-2-vaccinated adults. 
Length of Participation 
Cohort A participants - Screening period of up to 28 days and Vaccination Visit 
through Final Visit of up to 394 days; a total of up to 422 days 
Cohort B participants - Screening period of up to 28 days and Vaccination Visit 
through Final Visit to 366 days; a total of up to 394 days 
Intervention 
The study will evaluate 3 investigational vaccines: 
• 
ARCT-021: A self-amplifying RNA vaccine coding for wild-type 
ancestral strain spike antigen 
• 
ARCT-154: A self-amplifying RNA vaccine coding for the D614G 
variant of ancestral strain spike antigen 
• 
ARCT-165: A self-amplifying RNA vaccine coding for the SARS-
CoV-2 Beta variant of SARS-CoV-2 and also containing the D614G 
variant mutation 
• 
All 3 investigational vaccines will be administered as a 5-µg dose in 
0.5-mL volume administered intramuscularly into the deltoid muscle. 
If additional cohorts are added, the dose of each study vaccine will not 
exceed 5 µg at each injection.  
• 
Participants will receive 1 or 2 doses based on cohort assignment. 
• 
Cohort A participants will receive 2 doses (28 days apart) of ARCT-
165, ARCT-154, or ARCT-021. 
• 
Cohort B participants will receive 1 dose of ARCT-165, ARCT-154, 
or ARCT-021. 
Primary Objectives and 
Primary Endpoints 
Objective 1: To describe the safety and reactogenicity of 3 investigational 
SARS-CoV-2 self-amplifying RNA vaccines 
Endpoint 1: Safety will be summarized for each vaccination as the number and 
percentage of participants with the following: 
a. 
Any solicited local or systemic adverse event (AE) collected for 7 
days after each study vaccination, which will be assessed by toxicity 
grade 
b. Any unsolicited AE collected for 28 days after each study vaccination, 
which will be assessed by severity and relationship to study vaccine 
c. 
Any medically attended adverse events (MAAEs), AEs leading to 
discontinuation from study vaccine/study withdrawal, or serious 

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adverse events (SAEs) through Final Visit/Early Termination (ET) 
Visit (Final Visit is defined as 365 days after the last study vaccine 
dose) 
Objective 2: To describe the immunogenicity (antibody responses) of 
3 investigational SARS-CoV-2 self-amplifying RNA vaccines 
Immunogenicity (antibody responses) will be evaluated after vaccination using 
the following assays and approaches: 
Endpoint 2: SARS-CoV-2 neutralizing antibody titer by pseudoviral 
microneutralization assay (ancestral strain, D614G variant, and SARS-CoV-2 
Betavariant [as available]). Assay results will be evaluated as follows: 
a. Geometric mean concentrations (GMCs) at each time point designated in the 
Schedule of Assessments. 
b. Geometric mean fold rise (GMFR) from before vaccination to each 
subsequent time point evaluated after vaccination. 
c. 
Proportion of participants achieving ≥4-fold rise from before 
vaccination to each subsequent time point evaluated after vaccination. 
d. GMC ratio (ARCT-021/ARCT-165, ARCT-165/ARCT-154, and 
ARCT-021/ARCT-154) measured at all time points evaluated. 
e. 
Exploratory: Neutralizing antibody responses to other SARS-CoV-2 
variant strains may also be performed and will be described in the 
statistical analysis plan (SAP). 
Endpoint 3: Binding antibody concentration: Immunoglobulin G (IgG) to 
variant-specific SARS-CoV-2 full-length spike, receptor-binding domain 
(RBD), and nucleocapsid (N) antigens measured by Meso Scale Discovery 
(MSD) multiplex assay (ancestral strain, D614G variant, SARS-CoV-2 Beta 
variant, as available) will be evaluated as follows: 
a. Geometric mean concentrations (GMCs) at each time point designated in the 
Schedule of Assessments. 
b. GMFR from before vaccination to each subsequent time point after 
vaccination. 
c. Proportion of participants achieving ≥4-fold rise from before vaccination to 
each subsequent time point after vaccination. 
d. Exploratory: Binding antibody responses to other SARS-CoV-2 variant 
strains may also be performed and will be described in the SAP. 
Exploratory Objective(s) 
and Corresponding 
Endpoint(s) 
Objective 1: To describe and to compare the cell-mediated immune response to 
different variants of SARS-CoV-2 following vaccination with 3 investigational 
SARS-CoV-2 self-amplifying RNA vaccines 
Endpoint 1: CMI responses will be measured at designated time points using 
one or more of the following assays:  
a. Enzyme-linked immune absorbent spot (ELISpot; Oxford Immunotec T-
spot) assay. 
b. Intracellular Staining using Flow Cytometry (ICS, Oxford Immunotec) 
c. 
Fc effector function: Antibody-mediated cytotoxicity will be measured 
using surrogate assays measuring CD16 signaling at some or all time 
points designated in the Schedule of Assessments. 
d. Additional assays of CMI function may be performed and will be 
specified in the SAP prior to analysis. 

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Objective 2: To summarize the incidence of COVID-19 cases in enrolled study 
participants  
Endpoint 2: Virologically confirmed COVID-19 cases occurring after study 
enrollment will be summarized according to the following: 
a. Onset within the first 14 days after receipt of the first study vaccination 
b. Onset at least 14 days after receipt of the first study vaccination 
c. Severity (severe versus non-severe cases) as defined by Food and Drug 
Administration (FDA) criteria 
Objective 3: To provide sera for use for exploratory passive transfer studies in 
animals 
Endpoint 3: No formal analysis of endpoints will be performed in this study. 
Number of Sites 
At least 1 study site in one or more of the following countries - Singapore, 
South Africa and the US 
Safety Review Committee 
A blinded SRC comprising the Principal Investigator (PI) at each site (as 
applicable), the contract research organization (CRO) medical monitor, and the 
Sponsor Medical Monitor (or designee) will review and monitor safety data 
from this clinical study and will be responsible for recommending decisions to 
proceed with dosing following review of safety data from sentinel participants 
in each cohort (including A1 and A2) and to proceed with second dosing of the 
study vaccine in Cohort A. In addition, the SRC will be responsible for 
approving recommendations to expand one or more cohorts or add one or more 
cohorts at lower doses. 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
3´ 
On the 3-prime end of the nucleotide sequence 
5´ 
On the 5-prime end of the nucleotide sequence 
ACE-2 
Angiotensin-converting enzyme 2 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
BP 
British Pharmacopeia 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMI 
Cell-mediated immunity 
COVID-19 
Coronavirus disease 2019 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
DNA 
Deoxyribonucleic acid 
DSPC 
1,2-distearoyl-sn-glycero-3-phosphocholine 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of Study 
ELISpot 
Enzyme-linked immune absorbent spot 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMC 
Geometric mean concentration 
GMFR 
Geometric mean fold rise 
GMTs 
Geometric mean titers 
HCP 
Health care provider 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HSA 
Health Sciences Authority (of Singapore) 
huACE-2 
human angiotensin converting enzyme-2 

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Abbreviation 
Definition 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICS 
Intracellular cytokine staining 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IM 
Intramuscular 
IRB 
Institutional Review Board 
LNP 
Lipid nanoparticle 
LUNAR® 
Arcturus’ proprietary LNP technology 
MAAE 
Medically attended adverse event 
MedDRATM 
Medical Dictionary for Regulatory Activities 
MDRD 
Modification to Diet in Renal Disease 
mRNA 
Messenger ribonucleic acid 
MSD 
Meso Scale Discovery 
N 
Nucleocapsid 
NCS 
Not clinically significant 
nsP 
Nonstructural protein 
PI 
Principal Investigator 
PPE 
Personal protective equipment 
PRNT 
Plaque reduction neutralization test 
PRNT50 
The titer of serum required to reduce the number of plaques by 50% in a 
PRNT assay 
PT 
Preferred Term 
RBD 
Receptor-binding domain 
RNA 
Ribonucleic acid 
S glycoprotein 
Spike glycoprotein 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome-coronavirus-2 (the strain of coronavirus 
that causes COVID-19) 
SC 
Subcutaneous 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
STARRTM 
Arcturus’ proprietary ‘Self-Transcribing and -Replicating RNA’ 
SUSAR 
Suspected unexpected serious adverse reaction 
sVNT 
Spike protein binding and neutralizing 
Tfh 
T follicular helper 
US 
United States 

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Abbreviation 
Definition 
USP 
United States Pharmacopeia 
VEEV 
Venezuelan equine encephalitis virus 
VS 
Vital signs 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential  
 

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1 
INTRODUCTION 
1.1 
Background 
In January 2020, a novel variant of coronavirus was identified as the cause of an outbreak of 
severe pneumonia in China. This virus, severe acute respiratory 
syndrome-coronavirus-2 (SARS-CoV-2), was identified as the causative agent of a broad clinical 
spectrum of disease. 
Both symptomatic and asymptomatic infections in humans are caused by the SARS-CoV-2 virus, 
which is a positive strand ribonucleic acid (RNA) virus. A serious manifestation of the infection 
is a viral pneumonia that can progress to acute respiratory distress syndrome (ARDS), respiratory 
failure, and death. Clinical symptoms relating to other organ systems have also been described 
(Zhang 2020; Zaim 2020). Risk factors for more severe disease include age, cancer, 
cerebrovascular disease, chronic kidney disease, chronic lung disease, dementia and other 
neurological conditions, diabetes, Down syndrome, heart conditions, human immunodeficiency 
virus (HIV), immunocompromised state, liver disease, obesity/overweight status, pregnancy, 
sickle cell disease/thalassemia, smoking, substance abuse disorders, and transplant (solid organ 
or bone marrow) (CDC 2021). Onset of severe lung disease often requires ventilatory support, 
and initial mortality rates as high as 25% to >90% were reported in these patients (Zhou 2020; 
Richardson 2020; Auld 2020; Phua 2020). More recently, mortality rates have reduced as more is 
known about how best to manage severe disease with treatments such as recently authorized 
targeted monoclonal therapies (bamlanivimab, etsevimab, casirivimab, and imdevimab) and 
application of other therapeutic agents (remdesivir, tocolizumab, baricitinib, and corticosteroids) 
(NIH 2021). 
Over 150 million cases of coronavirus disease 2019 (COVID-19) have been confirmed 
worldwide, over 3.2 million people have died as of May 2021 (WHO 2021), and the number of 
cases continues to grow in most countries. In addition, variant strains with higher transmissibility 
(CDC 2021) and, in some cases, higher virulence (Hornby 2021) have emerged and are 
circulating in many countries. 
1.2 
Current Therapies for COVID-19 
COVID-19 is a complicated disease, and optimal management is still evolving. As such, a 
comprehensive discussion is beyond the scope of this document. However, a number of 
treatment guidelines exist (WHO 2020a; NIH 2021; Bhimraj 2020). Treatment of less severe 
disease involves isolation and is largely symptom management. Severe disease requires 
supplemental oxygen with or without mechanical ventilation, prevention of thromboembolic 
complications, and treatment of secondary infection. Progress has been made in the development 
and emergency use authorization of targeted monoclonal antibodies directed against 
SARS-CoV-2 virus (NIH 2021); however, the clinical application of these monoclonal 
antibodies is limited to non-hospitalized patients with mild-to-moderate symptoms and high risk 
of progression to severe COVID-19 (NIH 2021; FDA 2020a; FDA 2020b). Application of 
anti-inflammatory agents, such as steroids, interleukin-6 inhibitors, and Janus kinase inhibitors, 
has improved outcomes in hospitalized patients (NIH 2021). 
A critical component to addressing morbidity and mortality due to SARS-CoV-2 is the 
development of vaccines to prevent transmission of SARS-CoV-2 in order to further prevent the 

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emergence of resistant strains. In late 2020 and in early 2021, multiple companies have shared 
the results of pivotal studies examining vaccine candidates intended to prevent 
COVID-19 disease. This has led to the emergency use authorization approvals of several 
inactivated SARS-CoV-2 viral (Global Regulatory Partners 2021; Reuters 2021a; Washington 
Post 2020), SARS-CoV-2 peptide (Turkmenistan Today 2021), SARS-CoV-2 receptor-binding 
domain (RBD) dimer, adenoviral vector (EMA 2021a; EMA 2021b; Reuters 2021b; Burki 2020), 
and non-self-replicating messenger ribonucleic acid (mRNA) vaccines (FDA 2020b; FDA 
2020c; EMA 2021c). 
However, variant strains of SARS-CoV-2 that show features of displacing the original ancestral 
strain in circulation and/or of potential resistance to vaccine-induced antibodies based on 
ancestral strain antigens have emerged. The D614G variant appeared soon after the emergence of 
the ancestral strain and, associated with the point mutation of the spike protein, became a 
globally dominant variant of SARS-CoV-2 (Korber 2020). The SARS-CoV-2 Betavariant, which 
has the following lineage-defining mutations in the spike gene (D80A, D215G, E484K, K417N, 
N501Y, and A701V, has a high prevalence in South Africa and has shown resistance to several 
of the currently available vaccines, including BNT162b2 (Pfizer/BioNTech; Zhou 2021), 
mRNA1273 (Moderna; Wu 2021), and ChAdOx1 nCoV-19 (AstraZeneca; Zhou 2021; Madhi 
2021). Given the global spread of SARS-CoV-2, the emergence of variant SARS-CoV-2 strains, 
and logistical issues that have hindered the implementation of vaccination, there remains the 
unmet need for more vaccines to prevent transmission of SARS-CoV-2 and the need to develop 
vaccines with broad protection against a range of SARS-CoV-2 variants. 
1.3 
Therapeutic Rationale for ARCT-165 and ARCT-154 in Prevention of COVID-19 
SARS-CoV-2 is a novel virus belonging to the β-coronavirus genus. Coronavirus host cell 
infection is mediated by the attachment of the transmembrane spike glycoprotein 
(S glycoprotein) to host cell receptors and subsequent fusion with host cell membranes. The 
S glycoprotein forms homotrimers protruding from the viral surface (Tortorici 2019) and can be 
divided into 4 subdomains: S1, S2, transmembrane, and internal domain or endodomain. The 
S1 domain contains the RBD, which allows SARS-CoV-2 to bind directly to the peptidase 
domain of the angiotensin-converting enzyme 2 (ACE-2) receptor expressed on epithelial cells in 
the lungs, heart, kidneys, and gastrointestinal tract. Hence, antibodies to the S glycoprotein, 
especially the RBD, should block viral entry into cells expressing the ACE-2 receptor and 
thereby prevent infection. 
At least 4 conventional mRNA vaccines expressing the full-length SARS-CoV-2 S protein 
(Jackson 2020; Walsh 2020; Kremsner 2020) and the S protein RBD (Mulligan 2020; Sahin 
2020), respectively, have been reported to demonstrate both humoral and cell-mediated 
SARS-CoV-2 immune responses in early-phase clinical studies and protection following 
challenge with SARS-CoV-2 in non-human primate experiments (Corbett 2020; Van Doremalen 
2020; Mercado 2020; Patel 2020; Vogel 2020). Additionally, an RNA replicon vaccine coding 
the full-length SARS-CoV-2 S glycoprotein has been described as inducing a neutralizing 
antibody response in non-human primates that was similar to that seen in convalescent plasma 
(Erasmus 2020). Two conventional mRNA vaccines have established marked vaccine efficacy 
following 2 dose administrations, and the data from the pivotal studies establishing vaccine 
efficacy have led to the emergency use authorization and/or conditional marketing authorizations 
of these vaccines (see FDA 2020b; FDA 2020c; EMA 2020; EMA 2021a). However, the ability 

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of post-vaccination serum from these vaccines to neutralize the SARS-CoV-2 Beta and D614G 
variants is reduced (Zhou 2021; Wu 2021; Zou 2021), resulting in concerns that they may not 
provide such effective protection against this variant. Evaluation of additional mRNA vaccines 
and the pursuit of an immune correlate of protection remain ongoing at the time of this protocol 
finalization. 
1.4 
Mechanism of Action 
ARCT-021, ARCT-154, and ARCT-165, each contain Arcturus’ proprietary self-transcribing and 
-replicating RNA (STARRTM) technology, an RNA replicon construct based on the alphavirus, 
Venezuelan equine encephalitis virus (VEEV). The replicon for ARCT-021 (mRNA-2002) 
consists of a replicase gene and an RNA sequence encoding the ancestral strain SARS-CoV-2 S 
glycoprotein. The replicon for ARCT-165 (mRNA-2106) consists of a replicase gene and an 
RNA sequence encoding the SARS-CoV-2 S glycoprotein containing the SARS-CoV-2 Beta 
variant mutations (D80A, D215G, E484K, K417N, N501Y, and A701V) and, additionally, the 
D614G variant mutation. The replicon for ARCT-154 (mRNA-2105) consists of a replicase gene 
and an RNA sequence encoding the SARS-CoV-2 S glycoprotein containing the D614G variant 
mutation. The final drug product for all 3 vaccines includes an RNA replicon formulated with 
Arcturus’ proprietary lipid nanoparticle (LNP) technology (LUNAR®), including 4 lipid 
excipients. More detail relating to these vaccines is included in the Investigator’s Brochure (IB) 
(Arcturus 2022a).  
Alphaviruses are enveloped viruses with a positive strand RNA genome. Upon infection, the 
genomic RNA serves as a template for translation of 4 viral nonstructural proteins that form 
replicase complexes. These complexes synthesize viral genomic and subgenomic RNA, the latter 
of which serves as a template for translation of viral structural proteins, which then assembles 
with genomic RNA into new infectious viral particles. By replacing the RNA coding for 
structural proteins with RNA coding for a protein antigen of interest (in this case, the 
SARS-CoV-2 full-length S glycoprotein), the self-replicating machinery of the alphavirus can be 
used to generate sustained expression of the antigen, making such alphavirus replicon constructs 
an attractive tool for vaccines. These replicon RNAs, which do not encode the complement of 
structural genes necessary for assembly of virus particles and do not contain reverse transcriptase 
that converts the RNA genome into complementary deoxyribonucleic acid (DNA), replicate 
exclusively in the cytoplasm and cannot introduce their genetic material into the cellular genome. 
A more detailed description of the mechanism of mRNA amplification and the biochemical 
functions for each of the nonstructural proteins is described in Rupp 2015. 
On entry into the cytoplasm, the replicase gene, encoding the 4 nonstructural proteins (nsPs) 
(nsP1 to nsP4), is translated from mRNA, producing only the replicase proteins as a single 
polyprotein. The RNA-dependent RNA polymerase, nsP4, is released from the polyprotein and, 
in combination with the remaining nsP123 polyprotein, transcribes the complementary RNA 
strand of the entire mRNA, including the SARS-CoV-2 S glycoprotein RNA and poly A tail. The 
remaining polyprotein is processed into nsP1, nsP2, and nsP3 and, in combination with nsP4, 
transcribes only the 5´-G-methyl capped S glycoprotein mRNA from the 3´-5´ complementary 
strand of mRNA. The multiple copies of S glycoprotein mRNA transcript are then translated 
to produce full-length S glycoprotein, which is the vaccine antigen. Cleavage of the 
nsP123 polyprotein into its component nsPs terminates transcription of the complementary RNA 
(Rupp 2015). Remaining complementary RNA and S glycoprotein mRNA are then degraded by 

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intracellular nucleases, thereby terminating production of the antigen. Tissue distribution studies 
with ARCT-021, a similar replicon RNA construct coding for the ancestral strain 
SARS-CoV-2 spike protein showed that the mRNA is no longer detectable in most tissues by 
15 days post-dose. 
During the process of self-replication, a double-stranded RNA intermediate that has 
immunostimulatory properties activating the innate immune system is produced, ultimately 
enhancing the adaptive immune response to the expressed S glycoprotein and thereby behaving 
as an adjuvant. 
At the injection site, the LNP-formulated RNA is taken up by antigen-presenting cells and 
myocytes, the former of which traffic to regional lymph nodes where they present the vaccine 
antigen to CD4+ T cells and CD8+ T cells, resulting in their activation. Antigen can be detected 
in regional lymph nodes within hours of injection (Liang 2017; Lindsay 2019). 
Interleukin-2 from activated CD4+ T cells is subsequently important in the terminal 
differentiation of the activated, antigen-specific CD8+ T cells (Zhang 2011). Although the 
immunological events leading to antibody responses elicited by RNA vaccines have yet to be 
fully elucidated, T follicular helper (Tfh) cells, which are a subset of CD4+ cells, are required to 
develop germinal center responses and drive immunoglobulin class switch, affinity maturation, 
and long-term B cell memory (Pardi 2018), and strong induction of antigen-specific Tfh cells has 
been demonstrated following vaccination with mRNA vaccines (Lindgren 2017). 
1.5 
Clinical Study Experience with ARCT-165, ARCT-154, and ARCT-021 
ARCT-165 and ARCT-154 are based upon similar LNP-formulated replicon RNA vaccine 
construct, ARCT-021.  The LNP used in ARCT-021 contains the same lipids as the LNP for 
ARCT-165 and ARCT-154, and the RNA sequence of the replicase component of the replicon in 
ARCT-021 has 97% sequence homology with the replicase in ARCT-165 and ARCT-154. The 
principal difference in the sequences is that the mRNA in ARCT-021 codes for the ancestral 
strain spike protein, whereas the mRNA in ARCT-165 codes for the spike protein of the SARS-
CoV-2 Beta variant, which contains the D80A, D215G, E484K, K417N, N501Y, and A701V 
mutations and, additionally, the D614G variant mutation; the mRNA in ARCT-154 codes for the 
spike protein of the ancestral strain-D614G variant. Please refer to the IB (Arcturus 2022a) for a 
more detailed comparison of ARCT-021, ARCT-154, and ARCT-165. 
Because the principal differences between ARCT-021 and ARCT-165/ARCT-154 are primarily 
limited to the SARS-CoV-2 variant spike protein that is expressed, these changes only constitute 
a change of antigen within a platform, consistent with the “platform” approach described in 
DHHS 2020 and CHMP 2021 where, if the COVID-19 vaccine candidate is made with a 
platform technology used to manufacture an investigational vaccine in a previous study and is 
sufficiently characterized, it may be possible to use toxicology data (i.e., data from repeat-dose 
and biodistribution studies) and clinical data that have been obtained with other products using 
the same platform to support first-in-human (FIH) clinical studies. As such, Arcturus is using the 
non-clinical tissue distribution data, Good Laboratory Practices toxicology data, and prior human 
clinical study data generated with ARCT-021 to support the clinical development of 
ARCT-165 and ARCT-154. Please refer to the IB (Arcturus 2022a) for a description of the 
results of non-clinical studies conducted with ARCT-021. 

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At the time of finalization of this protocol (Version 3.0), 3 clinical studies had initiated 
evaluation of ARCT-021. These studies include a completed Phase 1/2 clinical study 
(ARCT-021-01) in healthy adult participants in Singapore (final report pending); an ongoing 
Phase 2 open-label extension study (ARCT-021-02) following on from ARCT-021-01, and a 
Phase 2 Study (ARCT-021-04) that is ongoing in the United States (US) and Singapore. The 
interim analyses of these studies, which have enrolled more than 600 participants, are described 
in detail in the IB. A Phase 1/2/3 study exploring ARCT-154 had initiated and fully enrolled over 
19,000 participants (interim data not yet available) and the ARCT-021-04 study has administered 
booster doses of either ARCT-021, ARCT-154, ARCT-165 to enrolled participants (interim 
booster data not yet available). See Section 1.7.1 for more information. 
1.6 
Rationale for Dose Regimen Selection 
A 2-dose priming regimen for ARCT-165 and ARCT-154 is supported by non-clinical 
pharmacology studies conducted in non-human primates, which showed a meaningful increase in 
anti-SARS-CoV-2 spike protein binding and neutralizing (sVNT) antibody titers together with 
broader neutralizing responses against all variants tested (SARS-CoV-2 Beta, P.1, B.1.1.7, and 
ancestral strain) following the second vaccination compared to the first.  
A single-dose boost regimen is supported by data from multiple other vaccines where booster 
vaccination following the priming vaccination series is typically given as a single injection. 
The 5-µg dose level selected is supported by safety and immunogenicity data collected in the 
Phase 1/2 study, ARCT-021-01, which was conducted with ARCT-021 and enrolled younger 
(≥21 to <56 years of age) and older (≥56 to ≤80 years of age) adults, and by safety data from 
interim analyses of the Phase 2 study, ARCT-021-04, which included 318 exposures at the 
5- and 7.5-µg doses in both younger and older adults. 
Data from the Phase 1/2 study demonstrated that post-vaccination increases in binding antibody 
responses are observable at all doses of ARCT-021 analyzed (1-, 5-, 7.5-, and 10-µg single-dose 
administration and 3- and 5-µg administered as 2 doses). However, the 10-µg dose was not 
adequately tolerated, and neutralizing antibody (plaque reduction neutralization test [PRNT50]) 
and T-cell responses following vaccination with ARCT-021 were most notable at the 5- and 
7.5-µg doses. Geometric mean titers (GMTs) for neutralizing antibody responses were similar at 
the 5- and 7.5-µg doses, and increases in SARS-CoV-2-S-protein-stimulated T-cell responses (as 
assessed by enzyme-linked immune absorbent spot [ELISpot]) were similar in the participants 
administered doses of 5- and 7.5-µg ARCT-021. CD8+ T-cell responses (as measured by 
intracellular cytokine staining [ICS]) following S-protein-peptide-pool stimulation were also 
similar in participants dosed with 5 µg and 7.5 µg of ARCT-021. However, CD4+ responses by 
ICS were generally greater in participants receiving 5 µg of ARCT-021 than those receiving 
7.5 µg of ARCT-021. 
ARCT-021 was generally safe and well tolerated at the 5- and 7.5-µg doses, and the solicited and 
unsolicited adverse event (AE) profiles were similar at these dose levels. Given the robust 
immune response, the acceptable safety profile observed following administration of ARCT-021, 
and the important advantages to lower dose administrations of vaccine in a pandemic setting to 
allow for greater distribution of limited vaccine supply, the 5-μg dose of ARCT-165 and 
ARCT-154 (given the similar construct to ARCT-021) offers the greatest advantages for 
evaluation in clinical studies. 

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Detailed study results are described in the IB (Arcturus 2022a). 
1.7 
Risk Benefit Assessment 
1.7.1 
Potential Risks 
The potential benefits and risks of ARCT-165/ARCT-154 are informed by the non-clinical and 
clinical studies conducted with ARCT-021 and non-clinical pharmacology studies conducted 
with ARCT-165 and ARCT-154. Detailed information about the potential benefits and risks and 
reasonably expected AEs of ARCT-021, ARCT-154, and ARCT-165 is provided in the IB 
(Arcturus 2022a). A summary of the potential risks of treatment with ARCT-021, ARCT-154, 
and ARCT-165, together with potential mitigation for these risks, is shown in Table 1.  As of 
protocol Version 3.0, the ongoing review of safety data from the ARCT-154-01 and ARCT-021-
04 had not identified any confirmed new risks with use of the ARCT-154 and ARCT-165 
vaccines. However, hypertension is being evaluated as a signal based on blinded safety data from 
the ARCT-154-01 study. 
Table 1 
Risk Minimization Measures Included in Clinical Studies of ARCT-021, 
ARCT-154, and ARCT-165 
Risk 
Mitigation 
Local and systemic reactogenicity 
• 
Vaccination via the IM route results in a lower rate of local 
reactions than ID or SC injection (Zhang 2015).  
• 
Local injection site reactions and systemic AEs, such as 
headache, fever, myalgia, or arthralgia, may be treated with 
acetaminophen (paracetamol), ibuprofen, or other 
non-steroidal anti-inflammatory drugs and/or with topical 
agents (e.g., ice or heat); however, administration of these 
agents within 24 hours prior to study vaccine administration 
is prohibited.  
• 
Individuals should be asked if they have a known history to 
any of the vaccine components prior to receiving any dose 
of ARCT-021, ARCT-154, or ARCT-165 vaccine. 
Individuals with a known severe allergy to any of these 
components should not be vaccinated. 
o 
ARCT-021 (frozen liquid formulation) includes nucleic acid 
(mRNA), four lipids (ATX-126, DSPC, cholesterol, 
PEG2000-DMG), 
, sucrose, 
 and 
sodium chloride. Note: this formulation is not in use in this 
study (ARCT-165-01). 
o 
ARCT-021/ARCT-154/ARCT-165 (lyophilized 
formulations) include nucleic acid (mRNA), four lipids 
(ATX-126, DSPC, cholesterol, PEG2000-DMG), sucrose, 
Kolliphor P188 Bio, potassium sorbate, and sodium chloride. 
• 
Allergic AEs may be treated with corticosteroids or H1/H2 
blockers as indicated and if not otherwise contraindicated. 
• 
For anaphylaxis or immediate-type hypersensitivity 
(≤4 hours after injection) of at least moderate severity 
following the administration of the study vaccine, 
subsequent doses of study vaccine will not be administered. 

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Table 1 
Risk Minimization Measures Included in Clinical Studies of ARCT-021, 
ARCT-154, and ARCT-165 
Risk 
Mitigation 
VAERD if subsequently infected with 
SARS-CoV-2 
• 
In ARCT-021-04 (Phase 2 study) and in Phase 3 studies, an 
independent DSMB or other safety committee will assess 
all cases of severe COVID-19 for imbalance in order to 
assess the risk of VAERD. The DSMB will make 
recommendations concerning modifying or stopping the 
study in order to manage any risk(s) identified. 
Myocarditis and Pericarditis 
• 
Participants are to be instructed to seek medical attention 
and notify study staff immediately should symptoms of 
myocarditis and /or pericarditis occur post-vaccination 
including chest pain, shortness of breath, or feelings of a 
fast-beating, fluttering or pounding heart. An unscheduled 
visit should be performed if feasible for further follow-up 
and investigation of potential myocarditis or pericarditis.  
• 
Participants reporting acute chest pain, shortness of breath, 
palpitations, or other signs of myocarditis or pericarditis 
within 6 weeks after vaccination must be referred to a 
cardiologist for evaluation and management. Cases of 
myocarditis and/or pericarditis will be followed until 
resolution of symptoms and abnormal test findings. 
• 
Individuals with a history of myocarditis, pericarditis or 
cardiomyopathy will be excluded from study participation. 
• 
A targeted questionnaire will be utilized to conduct follow-
up for potential cases of myocarditis and/or pericarditis. 
• 
Participants with a reported AE/SAE of myocarditis and/or 
pericarditis after study vaccine administration will be 
excluded from receiving further doses of study vaccine. 
• 
Pericarditis and/or myocarditis are considered AESIs and 
are thus subject to expedited reporting requirements. The 
investigator must notify the Sponsor within 24 hours of 
knowledge of any events.  
• 
A single myocarditis or pericarditis event considered to be 
related to study vaccination will result in a study pause 
according to study stopping rules. 
 
Note: Myocarditis and/or pericarditis has not been observed with 
ARCT-021, ARCT-154 or ARCT-165, but has been observed 
with other mRNA SARS-CoV-2 vaccines. 
Hypertension 
• 
Vital signs including blood pressure measurements are to be 
performed at multiple study visits including prior and 
following each study vaccine administration including at 
Days 4, 8 and 15 following any study vaccine 
administration to identify any clinically significant 
abnormalities or elevations in blood pressure. 
• 
Participants with a reported AE/SAE of hypertensive crisis 
after study vaccine administration will be excluded from 
receiving further doses of study vaccine. 

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Table 1 
Risk Minimization Measures Included in Clinical Studies of ARCT-021, 
ARCT-154, and ARCT-165 
Risk 
Mitigation 
Abbreviations: AE=adverse events; COVID-19=Coronavirus disease 2019; FDA=Food and Drug Administration; 
H=histamine; ID=intradermal; IM=intramuscular; SARS-CoV-2=severe acute respiratory syndrome 
coronavirus 2; SC=subcutaneous; Th1=T helper Type 1; Th2=T helper Type 2; VAERD=vaccine-associated 
enhanced respiratory disease 
Other potential risks of study participation beyond those associated with study vaccine include 
risks relating to blood sampling and breach of confidentiality. 
For currently available mRNA SARS-CoV-2 vaccines, myocarditis and pericarditis cases have 
been reported in males and females, most commonly within 7 days after the second dose. The 
incidence appears highest in males under the age of 40 and the observed risk is highest in males 
12 – 17 years of age. Cases have been reported in older males and in females as well, however, 
and also following other doses. Symptoms of myocarditis or pericarditis include chest pain, 
shortness of breath, or feelings of a fast-beating, fluttering or pounding heart. Subjects should 
seek medical attention and also notify study staff should symptoms occur post-vaccination. 
Although some reported cases required hospitalization with intensive care support, available data 
from short term follow-up suggest that most individuals had resolution of their symptoms with 
conservative management. Information is not yet available about potential long-term sequelae. It 
is not known whether the risk of myocarditis or pericarditis is increased following additional 
doses of mRNA vaccines. 
Blood sampling may be associated with transient asthenia, risk of fainting, and bruising or 
infection at the blood sampling site. Risk of infection is reduced by cleansing of the skin prior to 
blood withdrawal. Risk of fainting is reduced by performing blood sampling with the participant 
in a seated position. 
As study participation involves provision of personal health information by the participant to the 
site staff, measures are in place to reduce the risk of sharing of this personal information with 
others. Measures include maintenance of personal information in secure locations (e.g., locked 
file cabinets and/or password protected electronic filing systems). Only personnel involved in the 
conduct, oversight, monitoring, or auditing of this study will be allowed access to this personal 
information that is collected. All publications from this study will not disclose personal 
information of the participants. Study results disclosed in public locations, such as 
www.clinicaltrials.gov, will not include personal information of any enrolled participant. 
There may be other risks, discomforts, or side effects from participation in this study that are 
currently unknown. 
1.7.2 
Potential Benefits 
There is no direct benefit to study participants beyond a potential benefit to society resulting 
from improved understanding of investigational vaccines to prevent COVID-19 disease. 
Vaccination with ARCT-021, ARCT-154, and ARCT-165 may or may not provide protection 
against SARS-CoV-2 infection and COVID-19. As the study design includes receipt of 
vaccination with ARCT-021, ARCT-154, or ARCT-165, if any of these study vaccines are 

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effective in preventing COVID-19, then participants receiving that study vaccine will have the 
opportunity to derive clinical benefit. 
1.7.3 
Overall Risk: Benefit Assessment 
This protocol includes measures taken to minimize risks to potential study participants. In 
addition, the available non-clinical data with ARCT-165 and ARCT-154 and clinical data with 
ARCT-021 reflect that the self-replicating mRNA vaccine construct is immunogenic and well 
tolerated. This favorable risk/benefit profile supports evaluation of ARCT-021, ARCT-154, and 
ARCT-165 in SARS-CoV-2 vaccine-naïve participants as well as in previously 
SARS-CoV-2- vaccinated participants in this Phase 1/2 clinical study. 

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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objectives and Endpoints 
The primary objective(s) and endpoints are presented in Table 2. 
Table 2 
Primary Objectives and Endpoints 
Primary Objectives 
Endpoint Description 
1. To describe the safety and reactogenicity of
3 investigational SARS-CoV-2 self-amplifying
RNA vaccines
Endpoint 1: Safety will be summarized for each 
vaccination as the number and percentage of 
participants with the following: 
d. Any solicited local or systemic AE collected for
7 days after each study vaccination, which will be
assessed by toxicity grade
e.
Any unsolicited AE collected for 28 days
after each study vaccination, which will be
assessed by severity and relationship to
study vaccine
f.
Any MAAEs, AEs leading to
discontinuation from study vaccine/study
withdrawal, or SAEs through Final Visit/ET
Visit (Final Visit is defined as 365 days after
the last study vaccine dose)
2. To describe the immunogenicity (antibody
responses) of 3 investigational
SARS-CoV-2 self-amplifying RNA vaccines
Immunogenicity (antibody responses) will be 
evaluated after vaccination using the following assays 
and approaches: 
Endpoint 2: SARS-CoV-2 neutralizing antibody 
concentrations by pseudoviral microneutralization 
assay (ancestral strain, D614G variant, and SARS-
CoV-2 Beta variant [as available]). Assay results will 
be evaluated as follows: 
a. GMCs at each time point designated in the
Schedule of Assessments (Appendix 1 and
Appendix 2).
b.
GMFR from before vaccination to each
subsequent time point evaluated after
vaccination.
c.
Proportion of participants achieving ≥4-fold
rise from before vaccination to each
subsequent time point evaluated after
vaccination.
d.
GMC ratio (ARCT-021/ARCT-165,
ARCT-165/ARCT-154, and
ARCT-021/ARCT-154) measured at all time
points evaluated.
e.
Exploratory: Neutralizing antibody
responses to other SARS-CoV-2 variant
strains may also be performed and will be
described in the SAP.
Endpoint 3: Binding antibody concentration: IgG to 
variant-specific SARS-CoV-2 full-length spike, RBD, 
and N antigens measured by MSD multiplex assay 

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Table 2 
Primary Objectives and Endpoints 
Primary Objectives 
Endpoint Description 
(ancestral strain, D614G variant, SARS-CoV-2 Beta 
variant, as available) will be evaluated as: 
a. GMCs at each time point designated in the 
Schedule of Assessments (Appendix 1 and 
Appendix 2). 
b. GMFR from before vaccination to each 
subsequent time point after vaccination.  
c. 
Proportion of participants achieving ≥4-fold 
rise from before vaccination to each 
subsequent time point after vaccination. 
d. Exploratory: Binding antibody responses to 
other SARS-CoV-2 variant strains may also 
be performed and will be described in the 
SAP. 
Abbreviations: AE=adverse event; ET=early termination; GMC=geometric mean concentrations; 
GMFR=geometric mean fold rise; IgG=immunoglobulin G; MAAE=medically attended adverse events; 
MSD=Meso Scale Discovery; N=nucleocapsid; RBD=receptor-binding domain; RNA=ribonucleic acid; 
SAE=serious adverse event; SAP=statistical analysis plan; SARS-CoV-2=severe acute respiratory 
syndrome coronavirus 2. 
2.2 
Exploratory Objectives and Endpoints 
The exploratory objectives and endpoints are presented in Table 3. 
Table 3 
Exploratory Objectives and Endpoints 
Exploratory Objectives 
Endpoint Description 
1. To describe and to compare the cell-mediated 
immune response to different variants of 
SARS-CoV-2 viruses following vaccination with 
3 investigational SARS-CoV-2 self-amplifying 
RNA vaccines 
Endpoint 1: CMI responses will be measured at 
designated time points using one or more of the following 
assays (Appendix 1 and Appendix 2):  
a. ELISpot (Oxford Immunotec T-spot) assay. 
b. Intracellular Staining using Flow Cytometry 
(ICS, Oxford Immunotec) 
c. 
Fc effector function: Antibody-mediated 
cytotoxicity will be measured using surrogate 
assays measuring CD16 signaling at some or all 
time points designated in the Schedule of 
Assessments. 
d. Additional assays of CMI function may be 
performed and will be specified in the SAP prior 
to analysis. 

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Table 3 
Exploratory Objectives and Endpoints 
Exploratory Objectives 
Endpoint Description 
2. To summarize the incidence of COVID-19 cases in 
enrolled study participants 
Endpoint 2: Virologically confirmed COVID-19 cases 
occurring after study enrollment will be summarized 
according to the following: 
a. Onset within the first 14 days after receipt of the first 
study vaccination 
b. Onset at least 14 days after receipt of the first 
study vaccination 
c. 
Severity (severe versus non-severe cases) as 
defined by FDA criteria 
3. To provide sera for use for exploratory passive 
transfer studies in animals 
Endpoint 3: No formal analysis of endpoints will be 
performed in this study. 
Abbreviations: CMI=cell-mediated immunity; COVID-19=Coronavirus disease 2019; ELISpot=enzyme-linked 
immune absorbent spot; FDA=Food and Drug Administration; RNA=ribonucleic acid; SAP=statistical 
analysis plan; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.  
 

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3 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
This is a randomized, observer-blind, 2-cohort study evaluating the safety, reactogenicity, and 
immunogenicity of 3 investigational SARS-CoV-2 self-amplifying RNA vaccines. This study is 
intended for execution in one or more clinical study sites in one or more of the following 
countries – Singapore, South Africa and the US. 
The study will initially enroll approximately 72 adult participants divided into 2 cohorts (A and 
B) of 36 adult participants each based on previous vaccination status against SARS-CoV-2. 
Cohort A is further sub-divided into two sub-cohorts which include 12 participants who are 
seronegative at screening (Sub-cohort A1) and 24 participants who are seropositive at screening 
(Sub-cohort A2). Based on the review of interim analysis data, the study may be amended to 
further explore LUNAR SARS-CoV-2 vaccine development. The intended enrollment plan for 
additional participants will be shared with the applicable health authorities and ethics committee 
prior to initiation of enrollment.  
Within the first cohort (Cohort A), Sub-cohort A1 will include a total of 12 adult participants 
≥21 to ≤65 years of age who have not been previously vaccinated with a SARS-CoV-2 vaccine 
randomized in a 1:1:1 manner to receive two 5-µg doses of ARCT-165, ARCT-154, or 
ARCT-021 on Days 1 and 29. Sub-cohort A2 will include a total of 24 adult participants ≥21 to 
≤65 years of age who have not been previously vaccinated with a SARS-CoV-2 vaccine 
randomized in a 3:1 manner to receive two 5-µg doses of ARCT-154 or ARCT-021, 
respectively, on Days 1 and 29. 
The second cohort (Cohort B) will include a total of 36 adult participants ≥21 to ≤65 years of age 
who have been previously vaccinated (5 months or longer prior to study enrollment) with the 
BNT162b2 (Comirnaty) SARS-CoV-2 vaccine randomized in a 1:1:1 manner to receive a single 
5-µg dose of ARCT-165, ARCT-154, or ARCT-021, respectively, on Day 1. 
The first 3 participants (sentinel participants) enrolled in each of Sub-cohort A1 and Cohort B 
will be randomly assigned (1:1:1) to 1 of 3 study vaccines (ARCT-021, ARCT-154, and 
ARCT-165) administered in a blinded, parallel dosing fashion and the first 4 participants 
(sentinel participants) enrolled in Sub-cohort A2 will be randomly assigned (3:1) to ARCT-154 
or ARCT-021. Safety in each of these sentinel cohort participants (3 participants in Sub-cohort 
A1 and Cohort B each, and 4 participants in Sub-cohort A2) will be evaluated for 3 days after 
vaccination. These safety data will also be reviewed by a blinded Safety Review Committee 
(SRC) prior to the start of dosing of remaining participants in these cohorts.  
The study will also include the use of pausing and stopping rules that may pause or stop dosing 
of study vaccination based on any unexpected safety concerns. Further details of the pausing 
rules are provided in Section 4.2.4. 
Throughout the study, participants will be regularly assessed for safety using solicited and 
unsolicited AE collection, concomitant medication, vaccination, and procedure collection, 
physical examinations, vital signs (VS), body temperature and safety laboratory assessments as 
specified in the Schedule of Assessments. Participants will also undergo blood sampling for 
antibody and CMI responses to SARS-CoV-2 vaccines as well as for collection of sera for 
possible use in non-clinical passive transfer studies. Participants who develop symptoms of 

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COVID-19 or who are exposed to someone who has been diagnosed with COVID-19 or SARS-
CoV-2 infection will undergo testing to determine if the participant has SARS-CoV-2 infection. 
Safety, immunogenicity, and COVID-19 assessments will be performed through the duration of 
study participation as specified in the Schedule of Assessments. 
The overall design is shown in Figure 1. 
Figure 1 
ARCT-165-01 Study Schema 
 
 
Abbreviations: n=number; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SRC=Safety Review 
Committee. 
3.1.1 
Rationale for Study Design 
The SARS-CoV-2 pandemic that was declared in 2020 is continuing to cause global 
COVID-19 disease in 2021 despite success in developing and emergency use of vaccines 
directed against the SARS-CoV-2 strain. The control of the disease is complicated by both 
supply constraints and the emergence of variant strains that may be resistant to vaccination. 
Additional vaccines that can address priming and boosting vaccination as well as coverage 
against variants are needed. 
This Phase 1/2 study is designed to evaluate the safety, reactogenicity, and immunogenicity of 
3 investigational vaccines developed to address the SARS-CoV-2 virus and all developed on the 
same RNA manufacturing platform: ARCT-021 vaccine, which was developed against the 
original ancestral strain; ARCT-154 vaccine, which was developed to include the mutation seen 
in the ancestral strain-D614G variant; and ARCT-165 vaccine, which was developed to include 
the mutations seen in the SARS-CoV-2 Beta variant strain. These 3 investigational vaccines will 
be administered to individuals who either may or may not have been previously vaccinated 
against SARS-CoV-2. 

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As these study vaccines are built with the same LNP composition and very similar RNA 
composition to the ARCT-021 vaccine, which has been evaluated in 3 other clinical studies, the 
starting dose (5 µg) will be based on that previous clinical experience. ARCT-021 is a more 
pertinent comparator than placebo for the assessment of study objectives as its safety and 
immunogenicity have been well characterized; also, given the presence of the vaccination 
campaign in Singapore, South Africa and the US, it is difficult to ethically withhold active 
vaccine from placebo participants. The introduction of Sub-cohort A2 in protocol v3.0 allows for 
the further assessment of study vaccines ARCT-154 and ARCT-021 in SARS-CoV-2-vaccine-
naïve participants who are seropositive at baseline and will provide valuable safety and 
immunogenicity data in this important population. Given the stage of the pandemic and high 
seropositivity rates worldwide amongst unvaccinated populations, understanding the 
performance of the vaccines and gaining clinical experience in these settings will support 
ongoing and further clinical development efforts. Preliminary data from the vaccines evaluated 
in Cohort B of this study highlight that ARCT-154 appears to have broader antibody responses 
than the ARCT-165 vaccine (Arcturus 2022b, Arcturus 2022c). For this exploratory study, the 
shift in randomization will allow for more characterization of the ARCT-154 vaccine 
immunogenicity in individuals who have signs of prior exposure to one or more SARS-CoV-2 
strains.  ARCT-021 will be used primarily as a comparator for safety in this randomization 
scheme. 
This study is expected to inform future clinical development planning for SARS-CoV-2 vaccine 
candidates ARCT-154 and ARCT-165, which are intended for administration to individuals who 
may or may not have been previously vaccinated. 

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4 
PARTICIPANT SELECTION AND WITHDRAWAL CRITERIA 
4.1 
Selection of Study Participants 
Approximately 72 participants ≥21 to ≤65 years of age will initially be enrolled (up to a 
maximum of 144 adults ≥21 to ≤80 years if additional cohorts are added). Cohort A participants 
will not have previously received SARS-CoV-2 vaccinations while participants in Cohort B will 
have received 2 doses of the BNT162b2 SARS-CoV-2 vaccine at least 5 months prior to study 
enrollment.  
Participants who withdraw from the study after randomization may be replaced. 
Deviations from the inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or participant safety. 
Therefore, adherence to the eligibility criteria as specified in the protocol is essential. 
Participants officially enter the Screening Period following documentation of their informed 
consent either directly or via a legally authorized representative. 
Screen failures are individuals who fail to meet all inclusion criteria or who meet at least 1 of the 
exclusion criteria.  
Rescreening will be permitted for the following circumstances:  
• Expiry of the Screening Visit window without enrollment for an individual who 
otherwise appeared eligible for study participation 
• Screening safety laboratory assessments may be repeated up to twice if the first value is 
inconsistent with previously documented laboratory results and subject to the review and 
approval of the Medical Monitor.  
Note: A fever the day before Screening/First Visit does not result in a Screening failure, but it 
would result in a delay of study vaccine administration. 
4.1.1 
Inclusion Criteria 
Each participant must meet all of the following criteria to be enrolled in this study: 
Consent and Compliance 
1. Individuals or legally authorized representatives must freely provide consent to study 
participation.  
2. Individuals must agree to comply with all study visits and procedures (including blood, 
nasopharyngeal swabs, Diary Card completion, receipt of telephone calls from the site, 
willingness to be available for unscheduled clinic visits). 
3. Individuals of childbearing potential that are sexually active in relationship(s) must be 
willing to adhere to contraceptive requirements. Refer to Appendix 4 (Contraceptive 
Guidance) for further details. 
4. Individuals willing to comply with study prohibitions and refrain from blood donation 
throughout study participation. 

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Age and Gender 
5. Male, female, or transgender adults ≥21 to ≤65 years of age (Cohorts A and B) at 
enrollment. 
Type of Participant 
6. Cohort B only: Individuals who have received 2 doses of BNT162b2 (Comirnaty) 
vaccine (5 months or longer prior to study enrollment). 
7. Sub-cohort A2 only: Screening SARS-CoV-2 nucleocapsid binding antibody test results 
that are positive (all countries). 
8. Individuals with body mass index of ≥18 to ≤35 kg/m2 at Screening. 
9. Females: Must be non-pregnant and non-lactating. 
4.1.2 
Exclusion Criteria 
Participants meeting any of the following criteria will be excluded from the study: 
Prior/Concomitant Therapy 
1. Cohort A only: Individuals who have previously received ANY investigational or 
authorized MERS-CoV, SARS-CoV, and SARS-CoV-2 vaccines (including ARCT-021).  
2. Cohort B only: Individuals who have the following: 
a. Previously received BNT162b2 but have not received 2 doses within at least 
5 months prior to study enrollment 
b. Previously received another authorized or investigational vaccine (including 
ARCT-021) 
3. Individuals receiving treatment with another investigational drug, biological agent, or 
device within 30 days of Screening, or 5 half-lives of investigational drug, whichever is 
longer; or currently enrolled in or plans to participate in another clinical study with an 
investigational agent during the study period. 
4. Individuals who have plans to receive off-study COVID-19 vaccines during the study 
period. 
5. Individuals who have received a live replicating vaccine within 28 days prior to first 
study vaccination or a licensed inactivated or non-replicating vaccine within 14 days 
prior to first study vaccination.  
Medical Conditions 
6. Individuals with significant infection or other acute illness, including body temperature of 
>100.4°F (≥38.0°C) on the day prior to or on Day 1. See Section 4.2.1. 
7. Individuals with a known history of COVID-19 disease or asymptomatic 
SARS-CoV-2 infection (For Sub-cohort A1 and Cohort B only). 
8. Individuals who are pregnant or breastfeeding. 
9. Individuals with a known history of anaphylaxis, urticaria, or other significant adverse 
reaction to the study vaccines or its excipients. Refer to the IB for list of vaccine 
components. 
10. Individuals with a known history of anaphylaxis to other vaccines. 
11. Individuals with clinically significant abnormalities in medical history or physical 
examination, including but not limited to, the following: 

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a. Respiratory disease (e.g., chronic obstructive pulmonary disease [COPD], asthma) 
requiring daily medications or oxygen currently or any treatment of respiratory 
disease exacerbations (e.g., COPD or asthma exacerbation) warranting hospitalization 
or an emergency room visit or supplemental oxygen in the last 5 years. 
b. Significant cardiovascular disease (e.g., congestive heart failure, cardiomyopathy, 
ischemic heart disease) or history of myocarditis or pericarditis. 
c. Neurological or neurodevelopmental conditions (e.g., migraines, epilepsy, stroke, 
seizures in the last 3 years, encephalopathy, focal neurologic deficits, Guillain-Barré 
syndrome, encephalomyelitis or transverse myelitis). 
d. Significant hematologic abnormalities (e.g., sickle cell disease, beta thalassemia, 
coagulation disorders). 
e. Major surgery within the past 6 months. 
12. Individuals with a history of chronic liver disease. 
13. Individuals with a history of autoimmune disease or immunodeficiency. See Appendix 6 
for details. 
14. Individuals using systemic corticosteroids exceeding 10 mg/day of prednisone equivalent, 
allergy injections, immunoglobulin, interferon, immunomodulators, cytotoxic drugs, or 
other similar or toxic drugs. The use of low-dose topical, ophthalmic, inhaled, and 
intranasal steroid preparations will be permitted. 
15. Individuals who have received immunoglobulins and/or any blood or blood products 
within the 4 months before the first study vaccine administration or at any time during the 
study. 
16. Individuals with a known history of or positive Screening test for HIV, hepatitis C, or 
chronic hepatitis B. 
17. Individuals with uncontrolled hypertension (blood pressure of >160/100 mm Hg). 
18. Individuals with cancer within 5 years prior to Screening, except for basal or squamous 
cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully 
treated. 
Diagnostic Tests 
Individuals with the following abnormal Screening laboratory results:  
19. Sub-cohort A1 only: SARS-CoV-2 nucleocapsid binding antibody test results that are 
positive (to be performed in South Africa and the US only, given the higher rates of 
SARS-CoV-2 infection in these two countries) 
20. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl 
transferase (GGT), total bilirubin, or alkaline phosphatase >1.5 upper limit of normal.  
21. Hemoglobin <9.5 g/dL for females and <10.5 g/dL for males. 
22. Platelet count <100 × 109/L. 
23. Estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2 calculated by 
Modification to Diet in Renal Disease (MDRD) study equation. 
24. Other clinically significant abnormal (according to the judgment of the Investigator) 
Screening laboratory values. 
25. Individuals with Type 2 diabetes and Screening hemoglobin A1c >8.0%. 

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Other Exclusions 
26. Individuals who are Investigator site staff members, employees of Arcturus or the 
contract research organization (CRO) directly involved in the conduct of the study, or site 
staff members otherwise supervised by the Investigator or immediate family members of 
any of the previously mentioned individuals. 
4.1.3 
Screen Failures 
Screen failures are individuals who fail to meet all inclusion criteria or who meet at least 1 of the 
exclusion criteria.  
Rescreening will be permitted for the following circumstances:  
• Expiry of the Screening Visit window without enrollment for an individual who 
otherwise appeared eligible for study participation 
• Screening safety laboratory assessments may be repeated up to twice if the first value is 
inconsistent with previously documented laboratory results and subject to the review and 
approval of the Medical Monitor.  
• Screening vital sign assessments may be repeated twice if the first value is inconsistent 
with previously documented vital signs 
Note: A fever the day before Screening/First Visit does not result in a Screening failure, but it 
would result in a delay of study vaccine administration (see below). 
4.2 
Delaying or Discontinuing Study Treatment and Participant Withdrawal From the 
Study 
4.2.1 
Delay in Study Treatment 
Body temperature must be measured and the participant asked about recent antipyretic or 
analgesic use prior to each administration of study vaccine. 
The following events constitute criteria for delay of study vaccination and the window of delay 
specified forthwith: 
• Acute moderate or severe infection with or without fever at the time of dosing (delay: 
until afebrile for 48 hours and clinically recovered according to Investigator judgment) 
− Participants with minor illness and without fever may be vaccinated if deemed 
appropriate according to Investigator judgment. 
• Fever without signs of acute illness, defined as body temperature ≥38.0°C (100.4°F) 
(delay: Until afebrile for 48 hours) 
• Use of antipyretics or analgesics within 24 hours (delay: At least 24 hours).  
Vaccination may be performed once these criteria are no longer met, and this will not constitute 
a protocol deviation. 

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4.2.2 
Discontinuation of Study Vaccine (Participant) 
4.2.2.1 
Stopping Rules for Adverse Events in Individual Participants  
A participant must not receive further study vaccine administrations if they experience any of the 
following AEs: 
• Grade 3 solicited AEs (as confirmed by a blinded SRC review) 
• Any anaphylactic reaction 
• Severe related (possibly, probably, or definitely) unsolicited AEs 
• Any clinically apparent hypersensitivity episode that is considered at least moderate in 
severity, is considered possibly, probably, or definitely related to study vaccine 
administration (as assessed by the Investigator and review of the SRC) and has the following 
features:  
− is not confined to the injection site 
− is immediate in onset (within ≤4 hours after vaccination) OR if delayed, involves 
more than one organ system 
• Any serious adverse event (SAE) judged to be related (possibly, probably, or definitely) 
to study vaccine.  
• Myocarditis and/or pericarditis 
• Hypertensive crisis 
4.2.2.2 
Stopping Rules in Individual Participants for Other Circumstances 
Any participant that experiences any of the following after first study vaccination will not 
receive further injections of study vaccine:  
• Withdrawal of consent  
• Pregnancy  
• Any clinically significant medical condition that, in the opinion of the Investigator or the 
blinded SRC, poses an additional risk to the participant if he/she continues to participate in 
the study.  
4.2.3 
Withdrawal of Participant From Study 
Participants are free to withdraw from participation in the study at any time upon request, 
without any consequence. 
A participant will be withdrawn from the study if any of the following occur prior to first 
administration of study vaccine:  
• The participant requests to discontinue study participation. 
• Study vaccine is not administered. 
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study may include the following: 
• Refused further follow-up 
• Lost to follow-up 
• Death 

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• Study terminated by the Sponsor 
• Participant request 
• Investigator request 
• Protocol deviation 
• Opportunity to receive an approved COVID-19 vaccine 
For any participant terminating the study sooner than 60 days after last study vaccine 
administration, the following guidelines should be observed: 
• The participant should also be reminded about use of highly effective contraception until 
60 days following last study vaccine exposure.  
• Any pregnancy occurring this window should be reported to the Sponsor as soon as 
feasible.  
• Should the Principal Investigator (PI)/site become aware at any time of any death or 
pregnancy occurring in these participants it should be reported to Sponsor. 
The following guidance applies for participants who choose to exit the study to receive approved 
COVID-19 vaccine (Note: Participants can continue to be followed for safety even if they 
receive an authorized COVID-19 vaccine.): 
• The participant is advised to wait 4 weeks since the last study vaccination before seeking 
licensed vaccine. 
• Should the former participant experience any severe or serious or concerning AEs 
following receipt of the approved COVID-19 vaccine, they should notify the site. These 
events would be collected as post-study AEs. The participant should also report these AEs to 
the vaccine provider. 
The Investigator must capture the reason for withdrawal in the electronic Case Report Form 
(eCRF) for all participants. 
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the Investigator must document any such requests in the site 
study records and notify the Sponsor or CRO accordingly. 
If a participant withdraws consent and specifies no further contact with him/her or persons 
previously authorized by the participant to provide this information, this should be documented 
by the Investigator in the study source documents. In the event that vital status (whether the 
participant is alive or dead) is evaluated, publicly available information should be used to 
determine vital status only as appropriately directed in accordance with local law. 
4.2.4 
Study-Wide Pausing and Stopping Rules 
If any of the following is observed in the study, further administration of study vaccine to all 
participants will be paused until the blinded SRC has reviewed all relevant safety data and 
determined that it is safe for dosing with study vaccine to resume. Termination of the study will 
depend on evaluation of these safety data and the findings of the SRC. 
• Any SAE considered possibly, probably, or definitely related to study vaccine 
administration (as confirmed by SRC review) 
• Any anaphylactic AE following study vaccine administration 

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• Any clinically apparent hypersensitivity episode that is considered at least moderate in 
severity, is considered probably or definitely related to study vaccine administration (as 
confirmed by SRC review), and has the following features: 
− Is not confined to the injection site 
− Is immediate in onset (within ≤4 hours after vaccination) or, if delayed, involves 
more than 1 organ system 
• Any suspected or confirmed myocarditis, pericarditis, and/or myopericarditis event that is 
considered by the investigator to be possibly, probably, or definitely related to study vaccine 
administration or is temporally associated (within 6 weeks) with vaccine administration. 
• Any death due to SARS-CoV-2 infection or any severe (per the Food and Drug 
Administration [FDA] criteria [Appendix 7]) SARS-CoV-2 infection in a vaccinated 
participant.  
Events meeting Pausing Rule definitions will be referred to the SRC (which will remain blinded 
to the vaccine assignment), where the case details and the assessment of the event causality will 
be assessed. Should the SRC confirm that a Pausing Rule was met, Investigators will be 
immediately instructed to pause dosing, and the applicable health authorities will be notified 
within 1 business day of determination that a Pausing Rule has been met. 
Study vaccine administrations will continue to be paused while the case undergoes review. If 
review of the event(s) leads to SRC recommendation for an unblinded data review, a designated 
medical team (separate from the study team overseeing the study) from the Sponsor and 
including an independent medical reviewer will convene to review the unblinded details. After 
evaluation of these relevant data, this separate safety review team will make a recommendation 
to the SRC. The SRC will then document the decision of whether the study should be 
discontinued, should be modified prior to resumption of study vaccine administrations, or should 
continue without protocol modification. This recommendation will be provided to Health 
Authorities and Investigators prior to resumption of study procedures (if applicable). 
Should the study dosing pause or stop altogether, participants will continue clinic visits for safety 
assessments only through the Final Visit, as described in the Schedule of Assessments.  
4.2.5 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for scheduled visits 
or is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site 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 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 (where possible, 3 telephone calls over a 4-
week period and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in the 
participant’s study file. 

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If the participant continues to be unreachable, he/she will be considered to have withdrawn from 
the study. 
4.2.6 
Replacements 
Participants who withdraw from the study after randomization may be replaced. 
4.3 
Discontinuation of Study 
Although the Sponsor has every intention of completing the study, the Sponsor reserves the right 
to discontinue the study at any time for clinical or administrative reasons. 
The end of study (EOS) is defined as the date on which the last participant completes the last 
study visit (including the EOS visit and any additional long-term follow-up). Any additional 
long-term follow-up that is required for monitoring of the resolution of an AE or finding may be 
appended to the clinical study report (CSR). 

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5 
STUDY TREATMENTS 
5.1 
Method of Assigning Participants to Study Groups 
Participants will be randomized after all Screening assessments have been completed and after 
the Investigator has verified that they are eligible per criteria in Sections 4.1.1 and 4.1.2. No 
participant may begin study treatment prior to randomization and assignment of a unique 
participant identification number. 
The Sponsor or designee will prepare the randomization list, which will be provided to the study 
site unblinded pharmacist. 
5.2 
 Study Vaccine, Dosage, and Route of Administration 
ARCT-165, ARCT-154, and ARCT-021 study vaccines are LNP-formulated, RNA replicon 
vaccines. Details of the RNA composition of each study vaccine are described in Section 1.4. 
The nanoparticle composition includes 4 lipid excipients (ionizable cationic lipid; Arcturus 
proprietary lipid; neutral lipid, 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC]; cholesterol; 
and polyethylene glycol-lipid conjugate). 
The study vaccines are provided as lyophilized formulations in multi-dose glass vial 
presentations. The diluent for administration consists of 0.9% sodium chloride for injection, 
United States Pharmacopeia (USP), British Pharmacopeia (BP) or equivalent, and 
preservative-free. Sodium chloride (0.9%) will be provided by the study site. 
The study vaccines will be prepared by an unblinded trained site staff member in accordance 
with the Pharmacy Manual and outside of the view of blinded team members. The dose for 
administration to Cohorts A and B for all 3 study vaccines is 5 µg. 
Study vaccines will be matched for volume (0.5 mL) and presentation (1-mL syringe) prior to 
administration. 
Study vaccine (ARCT-165, ARCT-154, or ARCT-021) will be administered by intramuscular 
(IM) injection to the deltoid muscle by a health care provider (HCP) who will not be involved in 
assessments of any study endpoints. Study vaccine preparation and administration should be 
performed in an area outside of the view of blinded team members. Unblinded team members 
will not otherwise participate in other study-related procedures or assessments of the participant. 
The IM injection of the study vaccine will be into the lateral aspect of the deltoid muscle of the 
non-dominant arm, where possible. 
Epinephrine for subcutaneous (SC) injection, diphenhydramine for intravenous injection, and 
any other medications and resuscitation equipment for the emergency management of 
anaphylactic reactions must be available in close proximity to the room where the vaccination is 
administered. 
5.3 
Management of Clinical Supplies  
5.3.1 
Investigational Product Packaging and Storage 
The Sponsor will provide the Investigator with packaged study vaccine (ARCT-165, ARCT-154, 
and ARCT-021) containers labeled in accordance with specific country regulatory requirements. 

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Commercially available 0.9% sodium chloride for injection, USP, BP or equivalent, and 
preservative-free for dilution will be provided by the site. See the Pharmacy Manual for 
additional guidance. 
The study staff is required to document the receipt, dispensing, and return/destruction of study 
vaccine (ARCT-165, ARCT-154, and ARCT-021) supplies provided by the Sponsor. The study 
site must destroy or return for destruction all unused frozen vials of study vaccine (ARCT-165, 
ARCT-154, or ARCT-021) to the Sponsor or designee. Vials of study vaccine (ARCT-165, 
ARCT-154, or ARCT-021) should be destroyed by the study site or delegate only after drug 
accountability has been done by the unblinded study monitor. Destruction or return of study 
vaccine must be documented. 
Study vaccine temperature storage requirements and monitoring procedures are included within 
the Pharmacy Manual. 
5.3.2 
Study Vaccine Accountability 
The Investigator will maintain accurate records of receipt of all study vaccines (ARCT-165, 
ARCT-154, and ARCT-021) and diluent, including dates of receipt. In addition, accurate records 
will be kept regarding when and how much study vaccine is administered to each participant in 
the study. Only participants enrolled in the study may receive any study vaccine, and only 
authorized site personnel may supply or administer the study vaccine. Reasons for departure 
from the expected dispensing regimen must also be recorded. At the completion of the study, to 
satisfy regulatory requirements regarding drug accountability, all study vaccines will be 
reconciled and destroyed according to applicable regulations. Further guidance and information 
for the final disposition of unused study vaccines are provided in the Pharmacy Manual. 
5.3.3 
Other Supplies for Participant Use 
Study sites will distribute Sponsor-provided thermometers for body temperature measurement 
and rulers to measure injection site erythema and induration/swelling reactions. The 
measurements will be captured in the paper Diary Card provided by the site.  
5.4 
Overdose Management 
Study vaccine errors (including overdose, underdose, and administration error) must be 
documented as protocol deviations. A brief description should be provided of the deviation, 
including whether the participant was symptomatic (list symptoms) or asymptomatic, and 
whether the event was accidental or intentional. 
Dosing details should be captured on the appropriate source documents and on the Dosing eCRF. 
An overdose is the accidental or intentional administration of a study vaccine in an amount 
higher than the dose being studied. An overdose or incorrect administration of study vaccine is 
not itself an AE, but it may result in an AE. If the participant receives a dose of study vaccine 
that exceeds protocol specifications and the participant is symptomatic, the symptom(s) should 
be documented as an AE (Section 6.3.1.2). 
Should an overdose occur, the Investigator or designee should contact the Sponsor or designee 
within 24 hours. 

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There are no known treatments for potential overdose of study vaccine. Unless there is a user 
error leading to failure to administer any volume of study vaccine, “catch-up” study vaccine 
administrations will not be performed. 
5.5 
Blinding 
The study vaccines will be administered in an observer-blind fashion. 
Each of the study vaccines will be prepared by an unblinded trained team member and in 
accordance with the Pharmacy Manual. 
Unblinded personnel (of limited number) will be assigned to study vaccine accountability 
procedures and will prepare study vaccine for all participants. These personnel will have no 
study functions other than study vaccine management, documentation, accountability, 
preparation, and administration. They will not be involved in participant evaluations and will not 
reveal the identity of study vaccine to either the participant or the blinded study site personnel 
involved in the conduct of the study unless this information is necessary in the case of an 
emergency. 
• The HCP who administers the study vaccine will not be involved in assessments of any 
study endpoints. 
• Unblinded site monitors not involved in other aspects of monitoring will be assigned as 
the study vaccine accountability monitors. They will have responsibilities to ensure that sites 
are following all proper study vaccine accountability, preparation, and administration 
procedures. 
In order to maintain an observer-blind design, Investigators, site staff, participants, and CRO 
staff with oversight of study conduct will remain blinded to study vaccine assignments for the 
study duration. The Sponsor team with direct oversight of the study will remain blinded to 
individual participant study vaccine assignments until the time of study unblinding at the final 
analysis. All study participants will be followed for efficacy and safety endpoints through the 
planned study period, and results will be summarized in an EOS report. 
Sponsor staff who are not involved in direct oversight of the study may receive unblinded study 
data but will not share any unblinded information with the Sponsor team members overseeing the 
study. 
5.5.1 
Breaking the Blind  
An individual participant’s study vaccine assignment will not be unblinded to the Investigator or 
other blinded study site staff until the EOS unless awareness of the study vaccine assignment is 
relevant to the care of study participant. If the blind needs to be broken because of a medical 
emergency, the Investigator may unblind an individual participant’s treatment allocation.  
To the extent possible before unblinding, the Investigator should contact the Medical Monitor to 
discuss the medical emergency and the reason for revealing the actual treatment received by that 
participant. The study vaccine assignment will be unblinded through review of the randomization 
list provided to the study site unblinded pharmacist. Reasons for unblinding must be clearly 
explained and justified in the eCRF. The date on which the code was broken together with the 
identity of the person responsible must also be documented. 

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Participants who choose to receive vaccination with off-study COVID-19 vaccine will be 
encouraged to remain in the study, but those that choose to leave the study to pursue alternate 
vaccination will not be unblinded to study treatment unless there is an unexpected post-study 
SAE attributed as related to study vaccine by the study Investigator and for which the 
Investigator feels that awareness of the study vaccine assignment is relevant to the care of study 
participant. 
5.6 
Compliance with Study Treatment 
When participants are dosed at the site, they will receive the study vaccine directly from 
designated study site staff under medical supervision. The date and time of each dose 
administered will be recorded in the source documents and recorded in the eCRF. The receipt of 
study vaccine and study participant identification will be confirmed at the time of dosing by a 
member of the study site personnel other than the person administering the study vaccine. 
5.7 
Concomitant and Rescue Therapies and Procedures 
The use of concomitant therapies or procedures defined in the following section must be 
recorded on the participant’s eCRF. AEs associated with administration of these therapies or 
procedures must also be documented on the appropriate eCRF. 
5.7.1 
Concomitant Therapy 
Study site staff must question the participant regarding any medications taken (including 
herbal/homeopathic substances) and vaccinations received by the participant. The following 
information will be recorded in the eCRF: 
• Concomitant, non-study vaccinations administered as early as 28 days prior to receipt of 
the first dose of study vaccine and throughout the duration of study participation. 
• Concomitant medications and procedures are to be collected from Screening until 28 days 
after receipt of the last dose of study vaccine and if associated with an unscheduled visit. 
Concomitant medications and procedures associated with SARS-CoV-2 infection/COVID-
19, SAEs, medically attended adverse events (MAAEs), and AEs leading to discontinuation 
of study vaccine/ study withdrawal are to be collected through EOS participation.  
• Participants will be asked prior to vaccination and will be asked for 7 days after each 
vaccination in the paper Diary Card if they have taken any antipyretic or analgesics to 
prevent or treat study vaccine-associated side effects (AEs). Reported antipyretic or analgesic 
medications should be recorded in the source document by the site staff during the study 
visits or via other participant interactions (e.g., telephone calls). 
5.7.2 
Prohibited Concomitant Vaccines and Concomitant Therapy 
Receipt of non-study COVID-19 vaccine is prohibited for all enrolled participants while on 
study. Participants in Cohort B must have received both doses of BNT162b2 vaccine at least 
5 months prior to study enrollment.  
The use of the following concomitant medications and/or vaccines will not require withdrawal of 
the participant from the study but may determine a participant’s eligibility to receive a second 
dose or evaluability in the per-protocol analysis: 

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• Any investigational or non-registered product (drug or vaccine) other than the study 
vaccine used during the study period. 
• A non-study, live, attenuated vaccine administered during the period from 28 days before 
through 28 days after each dose of study vaccine or any approved inactivated or recombinant 
vaccine that was administered within 14 days before or after any dose of study vaccine. 
• Immunoglobulins and/or any blood products administered during the study period (except 
for treatment of COVID-19). 
• Medications that suppress the immune system, including corticosteroids administered at 
doses of 20 mg prednisone equivalent/day or higher, with the exception of medications used 
in the treatment of COVID-19. 
Section 4.2.1 describes delay in vaccination that will occur in the event of analgesic/antipyretic 
use prior to planned study vaccination. 
If a participant receives/takes a prohibited vaccine or drug therapy, the Investigator and the 
CRO's Medical Monitor will make a joint decision about continuing or withholding further 
dosing from the participant based on the time the medication was administered, the drug’s 
pharmacology and pharmacokinetics, and whether use of the medication will compromise the 
participant’s safety or the interpretation of data. It is the Investigator’s responsibility to ensure 
that details regarding concomitant medications and vaccines are adequately recorded in the 
eCRF. All medication and interventions necessary for the appropriate care for the study 
participant, particularly to treat COVID-19, should be administered and appropriately 
documented along with the AE. 
5.7.3 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
signing of the informed consent and the participant’s last protocol-specified study visit. 
All concomitant procedures must be recorded in the eCRF until 28 days after receipt of the last 
study vaccine. Thereafter, only concomitant procedures associated with an SAE, MAAE, AE 
leading to discontinuation of study vaccine/study withdrawal or treatment/evaluation of COVID-
19 cases will be entered in the eCRF. 
5.7.4 
Rescue Medication 
Epinephrine for SC injection, diphenhydramine for intravenous injection, and any other 
medications and resuscitation equipment for the emergency management of anaphylactic 
reactions must be available in close proximity in the room where the vaccination is administered. 
5.8 
Dose Modification 
No dose modifications will be allowed. 
5.9 
Intervention After the End of the Study 
No intervention will be provided to study participants at or after the EOS. 

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6 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Study Procedures 
6.1.1 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the general status 
of the participant, the skin of the intended study vaccine administration site, superficial lymph 
nodes, and cardiovascular, respiratory, gastrointestinal, and neurological systems.  
A directed physical examination will include, at a minimum, assessments of the skin of the 
intended/actual study vaccine administration site and/or any organ systems relevant to symptoms 
or AEs reported by the participant. Investigators should pay special attention to clinical signs 
related to previous serious illnesses. 
Physical examination is to be performed by a qualified health care practitioner designated by the 
Investigator. 
Any clinically significant change found during a physical examination should be evaluated for an 
underlying cause and the associated AE reported (Section 6.3.1). If no known cause is 
determined, the clinically significantly abnormal parameter may be reported as an AE. 
6.1.2 
Vital Signs and Body Temperature 
VS comprise heart rate (HR), blood pressure and respiratory rate. 
VS will be measured in a semi-supine position after 5 minutes of rest. VS and body temperature 
will be evaluated for clinical significance. Any clinically significant change in VS and body 
temperature should be evaluated for underlying cause and the associated AE reported. If no 
known cause is determined, the clinically significantly abnormal parameter may be reported as 
an AE. 
After each study vaccine administration, vital signs should be checked, and repeat vital signs 
should be taken if clinically indicated. 
6.1.3 
Pregnancy Testing 
Pregnancy testing will be performed on women who are not surgically sterile or confirmed 
postmenopausal. Pregnancy testing by urine dipstick is acceptable. Pregnancy testing will be 
performed and evaluated prior to each study vaccine administration. Refer to the Schedule of 
Assessments (Appendix 1 and Appendix 2 for Cohorts A and B, respectively) for further details. 
6.1.4 
Safety Blood Sampling 
Procedures for collection, handling, and storage of blood collected for safety assessments will be 
detailed in the Laboratory Manual. A list of laboratory analytes to be tested is included in 
Appendix 3. 
6.1.5 
Nasopharyngeal Swab Sampling 
Procedures for collection, handling, and storage of swabs collected for confirmation of 
SARS-CoV-2 infection will be detailed in the Laboratory Manual. 

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6.1.6 
Immunogenicity Blood Sampling 
Procedures for collection, handling, storage, and shipment of blood samples collected to assess 
the participant’s immune response will be detailed in the Laboratory Manual. 
6.1.7 
Diary Card Procedures 
Paper Diary Cards will be distributed to participants at each study vaccination visit. They will be 
instructed to complete the Diary Card for 7 days post-vaccination. Compliance will be checked 
at the study visits that are conducted 3 and 7 days after each study vaccination. Diary Cards are 
source documents and should be collected on Day 8 (Cohort A and Cohort B) and 
Day 36 (Cohort A) visits and maintained in the participants’ study files. Data from the diary card 
must be transcribed verbatim into the electronic data capture system. 
6.2 
Study Assessments and Visits 
6.2.1 
Cohort A Visits 
The Schedule of Assessments for Cohort A (including Sub-cohorts A1 and A2) is located in 
Appendix 1. 
Participants in Cohort A are followed for 12 months post-second dose of the study vaccine until 
Day 394. Study vaccines are administered on Days 1 and 29 where safety and immunogenicity 
assessments are also performed prior to administration of the study vaccine. Clinic visits 
including safety laboratories should occur 3, 7, and 28 days post-vaccination (Days 4, 8, 29, 32, 
36, and 57). Clinic visits including blood collection to measure the participant’s immune 
response to the study vaccine should occur on Days 15, 29, 43, 57, 119, 209, 299, and 394 (Final 
Visit). 
6.2.1.1 
Screening 
At Screening, individuals willing to participate in the study will:  
1. Review and provide informed consent 
2. Have an interview to review the following:  
a. Medical history 
b. Current symptoms 
c. Risks of recent exposure to COVID-19 and for symptoms of COVID-19 
d. AEs 
e. Concomitant medications, vaccinations, and procedures 
f. Availability for study procedures 
3. Have a complete physical examination 
4. Take a pregnancy test (if the participant is a woman of childbearing potential). Blood 
sampling may be performed for the pregnancy test if urine testing is not permitted by site 
policy. A follicle-stimulating hormone (FSH) test will be given to women suspected to be 
menopausal. Refer to Appendix 4. 
5. Undertake a blood draw for Screening laboratories (refer to Appendix 1 and Appendix 3 
for a list of Screening assessments) 

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6. Have their VS measurements taken (HR, respiratory rate, blood pressure, and body 
temperature) 
7. Have their height and weight measurements taken 
The information gathered from the interview and the assessments will be evaluated against 
inclusion/exclusion criteria to determine study eligibility. 
6.2.1.2 
Vaccination Visits (Days 1 and 29) 
Prior to receipt of the study vaccine, participants must complete: 
1. An interview to review the following:  
a. Current symptoms and AEs 
b. Risks of recent exposure to COVID-19 and for symptoms of COVID-19 
c. Concomitant medications, vaccinations, and procedures 
2. A complete physical examination 
3. Pregnancy testing (if the participant is a woman of childbearing potential). Blood 
sampling may be performed for pregnancy test if urine testing is not permitted by site 
policy.  
4. A blood draw for safety laboratories, immunogenicity assessments, and archival samples 
(refer to Appendix 1 for the Schedule of Assessments)  
5. VS measurements (HR, respiratory rate, blood pressure, and body temperature) 
The following should also be considered/undertaken before receipt of the study vaccine: 
6. The participant should be randomized if the participant remains eligible, if randomization 
has not been done previously (Day 1). 
7. If the participant remains eligible for the study vaccination, the study vaccine assigned 
should be administered by the vaccine administrator. 
8. The participant should be observed post-vaccination for at least 30 minutes and until 
stable. After each study vaccine administration, vital signs should be checked, and repeat 
vital signs should be taken if clinically indicated. 
9. The Diary Card should be distributed to the participant, and the participant should be 
trained on completion procedures and requirements for the Diary Card.  
If the participant is screened and enrolled on the same day (Day 1), Screening Visit procedures 
will not be repeated. 
6.2.1.3 
Post-vaccination Visits on Days 4, 8, 32, and 36 
At these visits, participants will have: 
1. An interview to review the following:  
a. AEs 
b. Risks of recent exposure to COVID-19 and for symptoms of COVID-19 
c. Concomitant medications, vaccinations, and procedures 
2. A review of Diary Card compliance 
3. A symptom-directed physical examination 
4. A blood draw for safety 

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5. VS measurements taken (HR, respiratory rate, blood pressure, and body temperature) 
6.2.1.4 
Post-vaccination Visits on Days 15 and 43 
At these visits, participants will have: 
1. An interview to review the following:  
a. AEs 
b. Risks of recent exposure to COVID-19 and for symptoms of COVID-19 
c. Concomitant medications, vaccinations, and procedures 
2. A symptom-directed physical examination 
3. A blood draw for immunogenicity assessments and archival samples 
4. VS measurements taken (HR, respiratory rate, blood pressure, and body temperature) 
6.2.1.5 
Post-vaccination Visit on Day 57 
At this visit, participants will have: 
1. An interview to review the following:  
a. AEs 
b. Risks of recent exposure to COVID-19 and for symptoms of COVID-19 
c. Concomitant medications, vaccinations, and procedures 
2. A symptom-directed physical examination 
3. A blood draw for safety laboratories, immunogenicity assessments, and archival samples 
(refer to Appendix 1 for the Schedule of Assessments) 
4. VS measurements taken (HR, respiratory rate, blood pressure, and body temperature) 
6.2.1.6 
Post-vaccination Visits on Days 119, 209, and 299 
At these visits, participants will have: 
1. An interview to review the following:  
a. AEs 
b. Risks of recent exposure to COVID-19 and for symptoms of COVID-19 
c. Concomitant medications, vaccinations, and procedures 
2. A symptom-directed physical examination 
3. A blood draw for immunogenicity assessments and archival samples (refer to Appendix 1 
for the Schedule of Assessments) 
4. VS measurements taken (HR, respiratory rate, blood pressure, and body temperature) 
6.2.1.7 
Final Visit on Day 394/Early Termination Visit 
At this visit, participants will have: 
1. An interview to review the following:  
a. AEs 
b. Risks of recent exposure to COVID-19 and for symptoms of COVID-19 
c. Concomitant medications, vaccinations, and procedures 

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2. A complete physical examination 
3. A blood draw for immunogenicity assessments and archival samples 
4. VS measurements taken (HR, respiratory rate, blood pressure, and body temperature) 
5. Counseling about long-term follow-up for SARS-CoV-2 infection (Early Termination 
[ET] visit) 
6.2.2 
Cohort B Visits 
The Schedule of Assessments for Cohort B is located in Appendix 2. 
Participants in Cohort 2 are followed for 12 months post study vaccine until Day 366. Study 
vaccine is administered on Day 1 where safety and immunogenicity assessments are also 
performed prior to administration of the study vaccine. Clinic visits including safety laboratories 
should occur 3, 7, and 28 days post-vaccination (Days 4, 8, and 29, respectively). Clinic visits 
including blood collection to measure the participants immune response to the study vaccine on 
Days 15, 29, 91, 181, 271, and 366 (Final Visit). 
6.2.2.1 
Screening 
At Screening, individuals willing to participate in the study will:  
1. Review and provide informed consent  
2. Have an interview to review the following:  
a. Medical history 
b. Current symptoms 
c. Risks of recent exposure to COVID-19 and for symptoms of COVID-19 
d. AEs 
e. Concomitant medications, vaccinations, and procedures  
f. Availability for study procedures 
3. Have a complete physical examination 
4. Take a pregnancy test (if the participant is a woman of childbearing potential). Blood 
sampling may be performed for a pregnancy test if urine testing is not permitted by site 
policy. A FSH test will be given to women suspected to be menopausal.  
5. Undertake a blood draw for Screening laboratories (refer to Appendix 2 and Appendix 3 
for list of Screening assessments) 
6. Have their VS measurements taken (HR, respiratory rate, blood pressure, and body 
temperature) 
7. Have their height and weight measurements taken.  
The information gathered from this interview and the assessments will be evaluated against 
inclusion/exclusion criteria to determine study eligibility. 
6.2.2.2 
Vaccination Visit on Day 1 
Prior to receipt of the study vaccine, participants must complete: 
1. An interview to review the following:  
a. Current symptoms and AEs 
b. Risks of recent exposure to COVID-19 and for symptoms of COVID-19 

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c. Concomitant medications, vaccinations, and procedures 
2. A complete physical examination 
3. Pregnancy testing (if the participant is a woman of childbearing potential). Blood 
sampling may be performed for pregnancy test (if urine testing is not permitted by site 
policy).  
4. A blood draw for safety laboratories, immunogenicity assessments, and archival samples 
5. VS measurements (HR, respiratory rate, blood pressure, and body temperature) 
The following should also be considered/undertaken before receipt of the study vaccine: 
6. The participant should be randomized if the participant remains eligible, if randomization 
has not been done previously. 
7. If the participant remains eligible for study vaccination, the study vaccine assigned 
should be administered by the vaccine administrator. 
8. The participant should be observed post-vaccination for at least 30 minutes or until 
stable.  
9. The Diary Card should be distributed to the participant, and the participant should be 
trained on completion procedures and requirements for the Diary Card.  
If the participant is screened and enrolled on the same day (Day 1), Screening Visit procedures 
will not be repeated. 
6.2.2.3 
Post-vaccination Visits on Days 4 and 8 
At these visits, participants will have: 
1. An interview to review the following:  
a. AEs 
b. Risks of recent exposure to COVID-19 and for symptoms of COVID-19 
c. Concomitant medications, vaccinations, and procedures 
2. A review of Diary Card compliance 
3. A symptom-directed physical examination 
4. A blood draw for safety laboratories 
5. VS measurements taken (HR, respiratory rate, blood pressure, and body temperature) 
6.2.2.4 
Post-vaccination Visits on Days 15, 29, 91, 181, and 271 
At these visits, participants will have: 
1. An interview to review the following:  
a. AEs 
b. Risks of recent exposure to COVID-19 and for symptoms of COVID-19 
c. Concomitant medications, vaccinations, and procedures 
2. A symptom-directed physical examination 
3. A blood draw for immunogenicity assessments and archival samples (refer to Appendix 2 
for the Schedule of Assessments) 
4. A blood draw for safety (Day 29 only) 
5. VS measurements taken (HR, respiratory rate, blood pressure, and body temperature) 

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6.2.2.5 
Final Visit Day 366/Early Termination Visit 
At this visit, participants will have: 
1. An interview to review the following:  
a. AEs 
b. Risks of recent exposure to COVID-19 and for symptoms of COVID-19 
c. Concomitant medications, vaccinations, and procedures 
2. A complete physical examination 
3. A blood draw for immunogenicity assessments and archival samples  
4. VS measurements taken (HR, respiratory rate, blood pressure, and body temperature) 
5. Counseling about long-term follow-up for SARS-CoV-2 infection (ET visit) 
6.2.3 
Unscheduled Visits (both Cohort A and B) 
Unscheduled visits include visits for specific safety issues and/or evaluation of possible 
COVID-19. These visits will ideally be performed in person; however, if local restrictions (e.g., 
lockdown) prevent this, they may be performed by telemedicine/telephone visit or home visit. 
Required procedures at these visits include AE and concomitant medication, vaccination, and 
procedure collection. For participants evaluated for COVID-19, samples should be collected for 
SARS-CoV-2 testing. Should the visit occur in person, the visit should also include evaluation of 
VS, body temperature, pulse oximetry (if feasible), and a symptom-directed physical 
examination. 
6.3 
Safety Assessments 
Safety assessments will include monitoring and recording of solicited and unsolicited AEs, 
MAAEs, AEs leading to discontinuation of the study vaccine/study withdrawal, SAEs, VS, and 
safety laboratory assessments. 
6.3.1 
Adverse Events 
6.3.1.1 
Definitions 
6.3.1.2 
Adverse Events 
The Investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to the study vaccine or their clinical significance. AE 
collection will begin after the signing of informed consent; however, AEs that occur prior to the 
administration of first dose of the study vaccine (i.e., non-treatment-emergent AEs) will be listed 
separately in the CSR. 
An AE is defined as any untoward medical occurrence associated with the use of a medicinal 
product in humans, whether or not considered related to the medicinal product. 
An AE, therefore, can be any of the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product 

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• Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition)  
• Recurrence of an intermittent medical condition (e.g., headache) not present at baseline 
• Any deterioration in a laboratory value or other clinical test (e.g., electrocardiogram 
[ECG], X-ray) that is associated with symptoms or leads to a change in study treatment or 
concomitant treatment or discontinuation from the study vaccine 
• AEs that are related to a protocol-mandated intervention, including those that occur prior 
to administration of the study vaccine (e.g., Screening invasive procedures such as biopsies) 
6.3.1.2.1 
Serious Adverse Events 
An SAE is defined as any event that: 
• Results in death 
• Is immediately life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the participant or may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
6.3.1.2.2 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is any SAE wherein a causal 
relationship to the study vaccine is at least reasonably possible and wherein the nature or severity 
of the AE is not consistent with the Reference Safety Information in the most current version of 
the Arcturus IB.  
6.3.1.2.3 
Medically Attended Adverse Events 
An MAAE is an AE that leads to an unscheduled visit (including a telemedicine visit) with an 
HCP (e.g., nurse, nurse practitioner, physician’s assistant, physician). This would include visits 
to a study site for unscheduled assessments (e.g., rash assessment, abnormal laboratory 
follow-up, COVID-19) and visits to HCPs external to the study site (e.g., urgent care, primary 
care physician).  
• Routine study visits will not be considered medically attended visits.  
• AEs observed in the immediate 30-min post-vaccination observation period will be 
regarded as MAAE if: 
− Treatment of the AE is required prior to discharge OR 
− Extension of observation is required due to clinical concerns or unstable clinical 
findings 

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Investigators will review unsolicited AEs for the occurrence of any MAAEs. All MAAEs must 
be reported in the eCRF. 
6.3.1.2.4 
Adverse Events Leading to Discontinuation of Study Vaccine/Study 
Withdrawal 
Any AE that leads to discontinuation of the study vaccine and/or withdrawal from the study will 
be regarded as an AE leading to discontinuation from the study vaccine and/or study withdrawal. 
Investigators will review reasons for discontinuation from the study vaccine or study withdrawal 
and report this on the appropriate eCRF page. 
6.3.1.2.5 
Adverse Event of Special Interest 
An adverse event of special interest (AESI), including both serious or non-serious events, is one 
of scientific and medical concern specific to the Sponsor’s product or program, for which 
ongoing monitoring and rapid communication by the Investigator to the Sponsor is appropriate. 
AESIs, as defined in the study protocol or associated documents, are required to be reported by 
the Investigator to the Sponsor immediately, no more than 24 hours after the Investigator’s first 
knowledge of the event.  
AESIs include myocarditis, pericarditis, and myopericarditis according to the Brighton 
Collaboration case definitions (Sexson Tejtel 2021). All participants should be instructed to 
report any acute chest pain, shortness of breath, palpitations, or other signs or symptoms of 
myocarditis or pericarditis occurring within 6 weeks after vaccination to site personnel as soon as 
possible (within 24 hours).  
In addition to reporting requirements to the Sponsor, the Investigator must refer participants 
reporting symptoms of myocarditis or pericarditis to a cardiologist for evaluation and 
management. In the event that the participant is unable to be seen by a cardiologist within 
24 hours, the participant should have an unscheduled visit within 24 hours, if medically stable, to 
evaluate the event and have cardiac markers drawn and a 12-lead ECG performed. A 
questionnaire will be provided to Investigators for case evaluation for any reported events. Cases 
of myocarditis and pericarditis will be followed until resolution of symptoms and abnormal test 
findings. 
Cases of myocarditis and/or pericarditis occurring in temporal association with vaccination will 
be considered potentially related, unexpected and serious, and are subject to expedited reported 
requirements as outlined in Section 6.3.1.2.13. 
6.3.1.2.6 
Solicited Adverse Events 
The term “reactogenicity” refers to selected signs and symptoms (“reactions”) occurring in the 
hours and days following a vaccination. These signs and symptoms are collected as solicited AEs 
from participants by use of the Diary Cards for 7 consecutive days following each study vaccine 
administration. 
The following solicited AEs are included in the Paper Diary: 
• Solicited local AEs: Injection site erythema, injection site pain, injection site 
induration/swelling, and injection site tenderness 

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• Solicited systemic AEs: Arthralgia, chills, diarrhea, dizziness, fatigue, fever (categorized 
by measured body temperature), headache, myalgia, and nausea/vomiting 
The occurrence of each of these solicited AEs is regarded as a study vaccine-related AE.  
Also solicited from participants but not categorized as an AE is the use of antipyretics and 
analgesics to prevent or treat solicited AEs. 
Solicited AEs are graded for severity according to scales defined in the US FDA’s Center for 
Biologics Evaluation and Research’s Guidance: Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (DHHS 2007, 
Appendix 5). 
Solicited AEs may also lead to circumstances that warrant collection of the events as unsolicited 
AEs. This includes any solicited AE that leads to any of the following: 
• A medically attended visit 
• An SAE 
• Discontinuation of the study vaccine 
• Withdrawal from the study 
• Any solicited AE that persists beyond 7 days after each study vaccine administration 
Furthermore, should the site determine that the participant experienced and failed to enter a 
Grade 3 or Grade 4 solicited AE in the Diary then this Grade 3 or Grade 4 solicited AE should be 
entered as an unsolicited AE in the eCRFs. 
6.3.1.2.7 
Unsolicited Adverse Events 
Unsolicited AEs are defined as any spontaneously reported or discovered AE. 
Unsolicited AEs will be collected in all participants who receive at least 1 dose of the study 
vaccine and are classified according to the following: 
• Mild, moderate, or severe 
• Whether or not the AE was categorized as an SAE, an MAAE, and/or an AE leading to 
discontinuation of the study vaccine/ study withdrawal 
• Whether or not the AE was related to the study vaccine or the study procedure in the 
judgment of the Investigator 
6.3.1.2.8 
Eliciting and Documenting Adverse Events 
AEs will be assessed from the time the participant signs the informed consent form (ICF) until 
exit from the study. Safety follow-up will be continued for 12 months after last injection of the 
study vaccine (up to last study visit). Any ongoing AE that a participant is experiencing at the 
time of Screening (e.g., intercurrent illness) should be captured as medical history. 
Solicited AEs will be solicited by Paper Diary for 7 days after each study vaccination in all 
participants. 
At every clinic visit and daily (for 7 days after each vaccination) by Paper Diary, participants 
will also be asked a standard nonleading question to elicit any medically related changes in their 
well-being. Any and all new changes to the participant’s health (including exacerbation of 
underlying disease) that are not solicited events will be regarded as an unsolicited AE. 

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In addition to participant observations, AEs identified from any study data (e.g., clinically 
significant findings or changes on physical examination, safety laboratory assessments, VS) or 
identified from review of other documents (e.g., participant Paper Diary) that are relevant to 
participant safety will be documented on the AE page on the eCRF. 
All unsolicited AEs will be collected for 28 days after each study vaccination. Unsolicited AEs 
that meet the protocol definition of MAAE, SAE, or AEs leading to discontinuation of the study 
vaccine/study withdrawal will be captured for the duration of study participation. 
If the Investigator learns of any SAE, including a death, at any time after a participant has been 
discharged from the study, and he/she considers the event to be reasonably related to the study 
vaccine or study participation, the Investigator must promptly notify the Sponsor. 
Solicited and unsolicited AEs will be coded by System Organ Class (SOC) and Preferred Term 
(PT) according to the Medical Dictionary for Regulatory Activities (MedDRATM). Note: 
Injection site tenderness will be coded only to the lower-level term, as there is no PT of injection 
site tenderness (it codes to a PT of injection site pain). 
6.3.1.2.9 
Assessment of Severity 
Solicited AEs: The intensity of solicited AEs will be graded for severity as Grade 0, 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), or Grade 4 (potentially life threatening). 
The severity of solicited AEs will be assessed according to scales based on the US FDA toxicity 
grading scales for vaccine clinical studies, as shown in Appendix 5.  
Unsolicited AEs: The severity of unsolicited AE will be rated as mild, moderate, or severe using 
the following criteria: 
Mild:  
• These events require minimal or no treatment and do not interfere with the participant’s 
daily activities. 
OR 
• An event usually transient in nature and generally not interfering with normal activities. 
Moderate: 
• These events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with normal functioning. 
OR 
• An AE that is sufficiently discomforting to interfere with normal activities. 
Severe: 
• These events interrupt a participant’s usual daily activities and may require systemic drug 
therapy or other treatment. Severe events are usually incapacitating. 
OR 
• An AE that is incapacitating and prevents normal activities. 
 

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6.3.1.2.10 
Assessment of Causality 
Solicited AEs: These are, by definition, regarded as related to the study vaccine. Therefore, 
causality is not assessed. 
Unsolicited AEs: The Investigator’s assessment of an unsolicited AE’s relationship to the study 
vaccine is part of the documentation process, but it is not a factor in determining what is or is not 
reported in the study. If there is any doubt as to whether a clinical observation is an AE, the 
event should be reported. 
The relationship or association of the study vaccine in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
• Unrelated: There is no association between the study vaccine and the reported event. 
• Possible: Treatment with the study vaccine caused or contributed to the AE, i.e., the event 
follows a reasonable temporal sequence from the time of study vaccine administration or 
follows a known response pattern to the study vaccine but could also have been produced by 
other factors. 
• Probable: A reasonable temporal sequence of the event with study vaccine administration 
exists and, based upon the known pharmacological action of the drug, known or previously 
reported adverse reactions to the drug or class of drugs, or judgment based on the 
Investigator’s clinical experience, the association of the event with the study vaccine seems 
likely. The event disappears or decreases on cessation or reduction of the dose of the study 
vaccine. 
• Definite: A definite causal relationship exists between study vaccine administration and 
the AE, and other conditions (concurrent illness, progression/expression of disease state, or 
concurrent medication reaction) do not appear to explain the event. The event reappears or 
worsens if the study vaccine is readministered. 
In addition to the Investigator’s assessment of relatedness, the Sponsor or designee will evaluate 
the available information and perform an independent assessment of all reported SAEs and 
determine if there is a reasonable possibility that the study vaccine is causally related to a 
reported SAE. 
6.3.1.2.11 
Reporting Adverse Events 
The recording of non-serious AEs will begin after the participant has signed the informed 
consent form (ICF) and will stop at the end of the participant’s follow-up period, which is 
defined as the participant’s last protocol-specified study visit. The Investigator will monitor each 
participant closely and record all observed or volunteered AEs in the electronic data capture 
(EDC) system. 
AEs that occur prior to administration of the study vaccine will be recorded as medical history. 
6.3.1.2.12 
Reporting Serious Adverse Events 
All SAEs (regardless of their relationship to the study vaccine) should be reported to the CRO 
Safety Department immediately (i.e., within 24 hours) after the study site’s first knowledge of 
the event. The contact information for SAE reporting can be found in the Investigator site file for 
the study. 

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Initial reports of SAEs will be entered in the eCRF and SAE eCRF. If the eCRF is not working 
for any reason, then SAEs should be reported using the paper SAE report form and submitted 
using the contact details in the Investigator site file for the study. When additional follow-up 
information becomes available, a follow-up SAE report (depending on the qualified event) must 
be completed by the Investigator or a qualified sub-Investigator as soon as possible. The 
Investigator is responsible for obtaining relevant detailed information to support all SAE reports, 
including records of inpatient and outpatient care, laboratory reports, and autopsy or medical 
examiner reports.  
6.3.1.2.13 
Regulatory Reporting Requirements for Serious Adverse Events Including 
Suspected Unexpected Serious Adverse Reactions 
The Sponsor is required to notify national regulatory agencies and (in conjunction with the 
Investigator) local regulatory authorities about the safety of a study vaccine under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements relating to 
safety reporting to the regulatory authority, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), and Investigators.  
The Sponsor or designee will promptly evaluate all SUSARs against cumulative product 
experience to identify and expeditiously communicate possible new safety findings to 
Investigators, applicable IRBs/IECs, and health authorities based on applicable legislation. 
To determine reporting requirements for SUSAR cases, the Sponsor or designee will assess the 
expectedness of these events using the reference safety information contained in the IB. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information from the Sponsor or designee will review and then file it as appropriate and 
will notify the IRB/IEC, if appropriate according to local requirements. 
6.3.1.2.14 
Follow-Up of Participants Reporting Adverse Events 
All AEs/SAEs must be reported in detail on the appropriate page on the eCRF and followed to 
satisfactory resolution, until the Investigator deems the event to be chronic or not clinically 
significant (NCS), the event is considered to be stable, or the participant is lost to follow-up. 
6.3.1.2.15 
Reporting Cases of COVID-19 or Asymptomatic SARS-CoV-2 Infection 
All participants will be reminded to contact the site within 24 hours for any signs or symptoms of 
COVID-19 as well as any known exposure to SARS-CoV-2/COVID-19 (see also Section 6.7). 
For those participants who terminate the study early, participants are requested to continue to 
report these events to the site and as soon as possible for up to 12 months since the last study 
vaccine administration. 
Any site that is made aware of a case of suspected COVID-19 or asymptomatic 
SARS-CoV-2 infection must be report this to the Sponsor or designee within 24 hours of 
Investigator notification.  
For participants who describe symptoms of or exposure to COVID-19, the site will complete a 
dedicated eCRF. For participants who terminate early from the study without withdrawing 
consent, this information will be captured on a paper case report form (CRF) (located in the 
Investigator Site File), which should be emailed or faxed to the Sponsor or designee.  

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The reporting instructions, including the email address or fax number for submitting paper 
forms, can be found in the Investigator Site File for the study. 
All events of COVID-19 will be reviewed by the Sponsor/designee to determine if the case 
definition of severe COVID-19 (Appendix 7) is met. 
6.3.1.2.16 
Laboratory Test Abnormalities 
Clinically significant abnormal laboratory test results, in the opinion of the Investigator, may 
constitute or be associated with an AE. Examples of these include abnormal laboratory results 
that are associated with symptoms or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia. Whenever possible, the 
underlying diagnosis should be listed in preference to abnormal laboratory values as AEs. 
Severity grading of abnormal test results should follow the grading of unsolicited AEs when the 
event is deemed clinically significant by the Investigator (Section 6.3.1.2.9). Clinically 
significant abnormalities will be monitored by the Investigator until the parameter returns to its 
baseline value or until agreement is reached between the Investigator and Sponsor Medical 
Monitor (or designee) that further follow-up is not required. Laboratory abnormalities deemed 
NCS by the Investigator should not be reported as AEs. Similarly, laboratory abnormalities 
reported as AEs by the Investigator should not be deemed NCS on the laboratory sheet. Where 
relevant, safety laboratory assessments will be analyzed by toxicity grade at the time of interim 
and final analysis. 
The Investigator is responsible for reviewing and signing all laboratory reports. The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
A list of laboratory analytes to be tested is included in Appendix 3. 
6.4 
Physical Examinations 
Any clinically significant change in physical examination should be evaluated for underlying 
cause and the associated AE reported. If no known cause is determined, the clinically 
significantly abnormal parameter may be reported as an AE. 
6.5 
Vital Signs and Body Temperature 
VS and body temperature will be evaluated for clinical significance. Any clinically significant 
change in VS or body temperature should be evaluated for an underlying cause and the 
associated AE reported. If no known cause is determined, the clinically significantly abnormal 
parameter may be reported as an AE. Severity grading of clinically significant abnormal VS 
should follow the grading of unsolicited AEs when the event is deemed clinically significant by 
the Investigator (Section 6.3.1.2.9). All collected VS will also be analyzed by toxicity grade at 
the time of interim and final analyses. 
6.6 
Pregnancy 
If a participant becomes pregnant or a pregnancy is suspected, or if a male participant believes 
his sexual partner has become pregnant during the study participation, the study site staff must be 
informed immediately. The pregnancy should be reported within 24 hours using a Pregnancy 
Notification Form and collected in the safety database. The Pregnancy Notification Form should 

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be sent to the CRO Safety Department. Follow-up information, including delivery or 
termination, should be reported within 24 hours of study site staff awareness. The contact 
information for pregnancy reporting can be found in the Investigator Site File for the study. 
Female participants: If a suspected pregnancy occurs while on the study in a female participant 
who has received the study vaccine, a pregnancy test will be performed. If the pregnancy test is 
positive, the participant will be encouraged to complete all study procedures except receipt of 
additional doses of the study vaccine (2-dose schedule). Regardless of continued study 
participation, the study physician will assist the participant in getting obstetrical care and the 
progress of the pregnancy will be followed until the outcome of the pregnancy is known (i.e., 
delivery, elective termination, or spontaneous abortion). The study vaccine assignment of the 
participant may be unblinded according to the judgment of the Investigator, provided unblinding 
informs a decision relating to pursuit of additional care or vaccination. If the pregnancy results in 
the birth of a child, the study site and Sponsor may require access to the mother and infant’s 
medical records to obtain additional information relevant to the pregnancy progress and 
outcome. A longer follow-up may be required if a newborn child experiences a medical 
condition. Follow-up will be performed to the extent permitted by the applicable regulations and 
privacy considerations, e.g., a pregnancy ICF may be required. 
Male participants: If the female partner of a male participant who has received the study vaccine 
becomes pregnant, the progress of the pregnancy of the male participant’s partner should be 
followed until the outcome of the pregnancy is known (i.e., delivery, elective termination, or 
spontaneous abortion). If the pregnancy results in the birth of a child, the study site and Sponsor 
may follow up with the mother and may request access to the mother and infant’s medical 
records to obtain additional information relevant to the pregnancy progress and outcome. A 
longer follow-up may be required if a newborn child experiences a medical condition. Follow-up 
will be performed to the extent permitted by the applicable regulations and privacy 
considerations, e.g., partner ICF may be required. 
6.7 
Surveillance for SARS-CoV-2 Infection 
In concert with the collection of AEs, participants will be interviewed for potential symptoms of 
COVID-19 disease, recent diagnosis of SARS-CoV-2 infection, and for potential exposure to 
COVID-19. The assessment of causality and severity for COVID-19 events will be evaluated in 
accordance with practices for other unsolicited adverse events. 
Potential symptoms of COVID-19 disease include, at a minimum, fever or chills, cough, 
shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of 
taste or smell, sore throat, congestion or runny nose, nausea or vomiting, and diarrhea. 
Exposure to COVID-19 is defined as a participant who has had close contact (within 6 feet 
[2 meters] for a total of 15 minutes or more) to a person with laboratory-confirmed 
COVID-19 (or clinically compatible illness) or to a person who has tested positive for 
COVID-19 (laboratory confirmed) but has not had any symptoms.  
This is irrespective of whether the person with COVID-19 or the contact was wearing a mask or 
whether the contact was wearing respiratory personal protective equipment (PPE). 
Participants should be reminded to contact the site within 24 hours if experiencing 
COVID-19-like symptoms or if exposed to a confirmed COVID-19 case.  

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Evaluation of participants with suspected COVID-19: 
6. If a participant reports symptoms of potential COVID-19, an unscheduled clinic visit 
should occur within 48 hours 
a. Reported symptoms include at a minimum: fever, chills, cough, shortness of breath or 
difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or 
smell, sore throat, congestion or runny nose, nausea or vomiting, and/or diarrhea. 
b. An exception to this is if the potential symptoms of COVID-19 are observed within 
7 days following study vaccination AND the Investigator determines that these 
symptoms are more consistent with vaccine adverse reactions and not COVID-19 
symptoms. 
c. If local policy does not allow an unscheduled in-person clinic visit, a RT-PCR or 
rapid antigen test may be performed and a telemedicine visit will be conducted. 
Alternatively the site can bring the test kit to point of care for sample collection and 
perform a telemedicine visit. 
7. If a participant reports a potential exposure to COVID-19, an unscheduled clinic visit 
should be performed within 48 hours 
a. Exposure to COVID-19 is defined as a participant who has had close contact (within 
6 feet [2 meters] for a total of 15 minutes or more) to a person with laboratory-
confirmed COVID-19 (or clinically compatible illness) or to a person who has tested 
positive for COVID-19 (laboratory confirmed) but has not had any symptoms.  
b. This is irrespective of whether the person with COVID-19 or the contact was wearing 
a mask or whether the contact was wearing respiratory personal protective equipment 
(PPE).  
c. If local policy does not allow an unscheduled in-person clinic visit, a RT-PCR or 
rapid antigen test may be performed and a telemedicine visit will be conducted. 
8. Starting the day after the Unscheduled Visit, the participant will be contacted daily by 
telephone until: 
a. An asymptomatic participant who has been exposed to COVID-19 has a negative RT-
PCR or rapid antigen test result.  
b. A participant with symptoms of COVID-19 and a positive RT-PCR or rapid antigen 
test clinically recovers or 14 days have passed since onset of symptoms. For 
participants with ongoing illness 14 days later, the COVID-19 event is to be followed 
to resolution and the frequency of calls and unscheduled visits is to be based on 
clinical discretion. 
c. A symptomatic participant has two negative test (RT-PCR or rapid antigen) results.  
d. Should a participant who was exposed to COVID-19, whose RT-PCR or rapid 
antigen test is negative go on to develop symptoms suggestive of COVID-19 within 
the next 14 days, the participant should have another Unscheduled Visit and receive 
repeat RT-PCR or rapid antigen testing. If COVID-19 is confirmed, the participant 
should undergo the follow-up described above. 
9. During daily check calls, the participant should be asked to verbally report the presence 
and severity of COVID-19-associated AEs, their highest body temperature and, if 

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feasible, lowest oxygen saturation for that day, and the Investigator should determine if 
medical attention is required due to worsening of COVID-19 symptoms. 
e. Daily check calls are to continue until the following: 
i. Asymptomatic participant: Until the first negative PCR or rapid antigen test result 
ii. Symptomatic participant: Until the second negative PCR or rapid antigen test 
result  
iii. Positive PCR or rapid antigen test: Continues until day 14 OR clinical resolution 
f. If a symptomatic participant’s first PCR or rapid antigen test is negative, repeat 
testing should ideally occur within 7 days of symptom onset. 
10. If COVID-19 positive and still symptomatic at day 14: the COVID-19 event will be 
followed to resolution and the frequency of calls and unscheduled visits will be based on 
clinical discretion. 
Participants who terminate from the study before completion will be told to inform the 
Investigator if they develop symptoms compatible with COVID-19 or a confirmed diagnosis of 
SARS-CoV-2 infection for 1 year after the last study vaccination so that they can be referred 
for appropriate medical follow up. Refer to Schedule of Assessments in Appendix 1 and 
Appendix 2. 

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7 
STATISTICAL CONSIDERATIONS 
For this study, statistical analysis will be primarily descriptive, and 95% confidence interval (CI) 
will be provided whenever applicable. No formal multiple comparison adjustments will be 
employed for multiple safety, immunogenicity, or exploratory endpoints. Nominal p-values and 
CIs may be computed for immunogenicity data analyses without controlling for multiplicity. 
This section summarizes the planned statistical analysis strategy and procedures for the study. 
The details of statistical analysis will be provided in the SAP, which will be finalized before the 
first interim analysis. If, after the study has begun, but prior to any unblinding, changes are made 
to primary and/or key secondary objectives/hypotheses or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with International Council for 
Harmonisation [ICH] Guideline E9). Changes to other secondary or exploratory analyses made 
after the protocol has been finalized, along with an explanation as to when and why they 
occurred, will be listed in the SAP or CSR for the study. Ad hoc exploratory analyses, if any, 
will be clearly identified in the CSR. 
7.1 
Sample Size Considerations 
No formal sample size calculation was performed. Based on experience in the 
ARCT-021-01 study, the size of individual study groups is considered sufficient to meet the 
objectives of the study while minimizing unnecessary participant exposure.  
7.2 
Populations 
Immunogenicity: All eligible enrolled participants who receive the specified number of doses of 
the study vaccine to which they are randomly assigned, within the predefined window, have at 
least 1 valid and evaluable immunogenicity result after the specified study vaccine dose, have 
blood collection within an appropriate window after the specified dose, and have no other major 
protocol deviations as determined by the Sponsor Medical Monitor. 
Safety: All enrolled participants who receive at least 1 dose of the study vaccine. 
7.3 
Definition of Baseline 
Unless specified otherwise, baseline will be the last value prior to administration of the study 
vaccine. 
7.4 
Interim Analysis  
Interim analyses may be performed by the Sponsor or designee for any cohort or cohorts after at 
least 12 participants within a cohort have reached at least the Day 29 time point.  
At each of these interim analyses, the data sets from immunogenicity assessments may not 
contain all participants’ data. However, these analyses are intended to inform additional clinical 
development considerations, including potential expansion of study enrollment to include 
additional cohorts. 
All available safety and immunogenicity data will be summarized. Blinded data will be shared 
with the blinded SRC, and unblinded data will be shared with designated Sponsor staff that are 
independent from study conduct. 

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For determination of additional dose cohorts to be added to the study design, it is expected that 
the Sponsor will select the dose, schedule, and population that will remain within the following 
boundaries: 
• Additional cohorts will include use of self amplifying study vaccine doses not to exceed 5 
µg at each injection. 
The study will remain blinded to site staff overseeing study assessments, blinded CRO 
personnel, and (with the exception of the Sponsor staff reviewing unblinded data) the Sponsor 
until the time of final analysis. 
Additional details regarding interim analyses will be specified in the SAP. 
7.5 
Planned Methods of Analysis 
7.5.1 
General Approach 
Statistical analyses will be primarily descriptive; no formal hypothesis testing will be conducted. 
Analyses will be performed using SAS® (Version 9.4 or higher). 
In general, clinical data and immunogenicity data will be summarized for the cohorts by study 
group and visit (where applicable), using descriptive statistics (n, mean, standard deviation, 
standard error, median, minimum, maximum, first and third quartiles for continuous variables, 
and frequencies and percentages for categorical variables). When categorical data are presented, 
the percentages will be suppressed when the frequency count is zero. Non-zero percentages will 
be rounded to one decimal place, except 100% will be displayed without any decimal places. 
Statistical testing, if performed, will be prespecified in the final SAP prior to the unblinding of 
participant data.  
7.5.2 
Demographic and Baseline Characteristics 
The safety population will be used for all analyses of disposition, demographics, and baseline 
characteristics. A separate summary of study populations will include the number of participants 
enrolled but not treated, if applicable. Disposition, demographics, and baseline characteristics, 
including medical history, will be summarized using descriptive statistics. 
7.5.3 
Safety Analysis 
Safety, reactogenicity, and safety laboratory assessments will be evaluated in the Safety set. 
Participants will be summarized according to the study vaccine that was received. 
Descriptive statistics will be provided for each solicited AE and for each study vaccine group. 
Local and systemic AEs from Day 1 through Day 7 after each vaccination will be presented by 
severity cumulatively using a 5-point toxicity grading scale (Grades 0 through 4). Descriptive 
summary statistics will include counts and percentages of participants with the indicated 
endpoint. 
Descriptive statistics will also be provided for abnormal hematology and chemistry laboratory 
values at Day 1 and at 3, 7 and 28 days following each dose of the study vaccine, including shifts 
in toxicity grading (DHHS 2007). Descriptive summary statistics will include counts and 
percentages of participants with the indicated endpoint. 

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Unsolicited AEs (including MAAEs, SAEs, and AEs leading to discontinuation/withdrawal) will 
be categorized according to MedDRA terms. Descriptive summary statistics (counts, 
percentages) will be provided for any unsolicited AE event in each study vaccine group. 
Missing solicited AE diary data will not be imputed; missing AE dates will be handled according 
to the rules defined in the SAP. 
7.5.4 
Immunogenicity Analyses 
Analyses will be conducted using the Immunogenicity set as defined for the specific assay under 
evaluation. Immunogenicity endpoints are described in Section 2 and will be summarized, by 
study vaccine group and time point, using descriptive statistics. If formal statistical testing is 
performed, it will be described in the SAP. 
The kinetics of immune response following vaccination with each study vaccination will be 
evaluated in binding, neutralizing antibody responses, and CMI through 365 days after the last 
vaccination. 
Participants who have a nucleocapsid (N) binding antibody test that is positive during the study 
will be identified, and sensitivity analyses of the immunogenicity data will be conducted with 
and without participants with this positive test. 
A full description of planned analyses for immunogenicity endpoints will be contained in the 
SAP prior to the time of the intended analysis. 
7.5.5 
Missing Data Handling 
Due to the exploratory nature of this study and the lack of statistical testing, missing data will not 
be imputed.  
7.6 
Monitoring Committees 
7.6.1 
Safety Review Committee 
A blinded SRC comprising the PI at each site (as applicable), the CRO medical monitor, and the 
Sponsor Medical Monitor (or designee) will review and monitor safety data from this clinical 
study and will be responsible for recommending decisions to proceed with dosing following 
review of safety data from sentinel participants in each cohort and to proceed with second dosing 
of the study vaccine in Cohort A. The SRC will also review all AEs that potentially meet the 
study stopping/pausing rules to confirm that study stopping/pausing rules have been met and, in 
the event of a stopping/pausing rule being met, will review safety data from all participants to 
determine whether it is safe to resume dosing or whether the study should be terminated, 
depending on findings and safety outcomes. In addition, the SRC will be responsible for 
approving recommendations to expand one or more cohorts or add one or more cohorts at lower 
doses. 

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8 
DATA QUALITY ASSURANCE 
This study will be conducted according to the ICH E6(R2) risk and quality processes described 
in the applicable procedural documents. The quality management approach to be implemented in 
this study will be documented and will comply with the current ICH guidance on quality and risk 
management. The Sponsor assumes accountability for actions delegated to other individuals 
(e.g., the CRO). 
8.1 
Data Management 
As part of the responsibilities assumed by participating in the study, the Investigator agrees to 
maintain adequate case histories for the participants treated as part of the research under this 
protocol. The Investigator agrees to maintain accurate eCRFs and source documentation as part 
of the case histories. These source documents may include laboratory reports and hospital 
records. 
All CRF information is to be filled in. If an item is not available or is not applicable, this fact 
should be indicated. Blank spaces should not be present unless otherwise directed.  
For eCRFs, investigative site personnel will enter participant data into the EDC system. The 
analysis data sets will be a combination of these data and data from other sources (e.g., 
laboratory data). 
Clinical data management will be performed in accordance with applicable CRO standards and 
data cleaning procedures to ensure the integrity of the data (e.g., removing errors and 
inconsistencies in the data). AE terms will be coded using MedDRA, an internal validated 
medical dictionary, and concomitant medications, vaccinations, and procedures will be coded 
using the World Health Organization (WHO) Drug Dictionary. 
8.2 
Data Disclosure 
The Sponsor will publicly disclose clinical study results through posting the results of studies on 
www.clinicaltrials.gov (ClinicalTrials.gov) and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results will be reported in an objective, accurate, balanced, and complete 
manner and are reported regardless of the outcome of the study or the country in which the study 
was conducted. 

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9 
ETHICS 
9.1 
Independent Ethics Committee or Institutional Review Board 
Country-specific regulations and the ICH guidelines require that approval from an IRB/IEC is 
confirmed before human subjects participate in research studies. Before study onset, the 
protocol, informed consent, advertisements to be used for the recruitment of study participants, 
and any other written information regarding this study to be provided to the participant or the 
participant’s legal guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC 
approvals and of the IRB/IEC compliance with ICH harmonised tripartite guideline E6(R2): 
Good Clinical Practice (GCP) will be maintained by the site and will be available for review by 
the Sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must identify 
the IRB/IEC name and address, the clinical protocol by title or protocol number or both, and the 
date approval or a favorable opinion was granted. 
The Investigator is responsible for providing written summaries of the progress and status of the 
study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The Investigator 
must promptly supply the Sponsor or its designee, the IRB/IEC, and, where applicable, the 
institution with written reports on any changes significantly affecting the conduct of the study or 
increasing the risk to participants. 
9.2 
Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, ICH GCP, and all applicable regulations. 
9.3 
Participant Information and Consent 
A written informed consent in compliance with local regulatory authority regulations or US 
Title 21 Code of Federal Regulations (CFR) Part 50 shall be obtained from each participant 
before entering the study or performing any unusual or nonroutine procedure that involves risk to 
the participant.  
An informed consent template may be provided by the Sponsor to investigative sites. If any 
institution-specific modifications to study-related procedures are proposed or made by the site, 
the consent should be reviewed by the Sponsor or its designee or both before IRB/IEC 
submission. Once reviewed, the consent will be submitted by the Investigator to his or her 
IRB/IEC for review and approval before the start of the study. If the ICF is revised during the 
course of the study, all active participants must be reconsented by signing the revised form if 
required by IRB/IEC. 
Before recruitment and enrollment, each prospective participant or his or her legal guardian will 
be given a full explanation of the study, allowed to read the approved ICF, and allowed to have 
any questions answered. Once the Investigator is assured that the participant/legal guardian 
understands the implications of participating in the study, the participant/legal guardian will be 
asked to give consent to participate in the study by signing the ICF. The authorized person 
obtaining the informed consent will also sign the ICF. 

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The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research (if applicable) and explain/address the exploratory research 
portion of the study. Participant medical records need to state that written informed consent was 
obtained. 
The Investigator shall retain the signed original ICF(s) and give a copy of the signed original 
ICF(s) to the participant or legal guardian. 

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10 
 INVESTIGATOR’S OBLIGATIONS 
The following administrative items are meant to guide the Investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB/IEC 
but will not result in protocol amendments. 
10.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the participant (or the participant’s legal guardian), except as necessary for 
monitoring and auditing by the Sponsor, its designee, the US FDA, or the IRB/IEC. 
The Investigator and all employees and coworkers involved with this study may not disclose or 
use for any purpose other than performance of the study any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the Sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. 
10.2 
Data Protection 
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in accordance with 
local data protection law, including laws regarding implementation of technical measures to 
ensure protection of participant data.  
Data collected must be adequate, relevant, and not excessive in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access. The study site will implement appropriate technical and organizational 
measures to ensure that the personal data can be recovered in the event of disaster. In the event 
of a potential personal data breach, the study site will be responsible for determining whether a 
personal data breach has, in fact, occurred and, if so, providing breach notifications as required 
by law. 
To protect the rights and freedoms of participants with regard to the processing of personal data, 
participants will be assigned a single, participant-specific numerical code (participant code). Any 
participant records or data sets that are transferred to the Sponsor will contain the participant 
code; participant names must not be transferred. All other identifiable data transferred to the 
Sponsor will be identified by this participant code. The study site will maintain a confidential list 
of participants who participated in the study, linking each participant code to his or her actual 
identity and medical record identification. In case of data transfer, the Sponsor will protect the 
confidentiality of participants’ personal data consistent with the clinical study agreement and 
applicable privacy laws. 

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10.3 
Financial Disclosure and Obligations 
Investigators and sub-Investigators 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. 
Neither the Sponsor nor the CRO is financially responsible for further testing or treatment of any 
medical condition that may be detected during the Screening process. In addition, in the absence 
of specific arrangements, neither the Sponsor nor the CRO is financially responsible for further 
treatment of the participant’s disease. 
10.4 
Investigator Documentation 
Prior to beginning the study, the Investigator will be asked to comply with ICH E6(R2) 
Section 8.2 and Title 21 of the CFR by providing all essential documents. 
10.5 
Study Conduct 
The Investigator agrees that the study will be conducted according to the principles of ICH 
E6(R2). The Investigator will conduct all aspects of this study in accordance with all national 
and local laws or regulations. Study information from this protocol will be posted on publicly 
available clinical study registers before enrollment of participants begins. 
10.6 
Adverse Events and Study Report Requirements 
The Investigator agrees to submit reports of SAEs and SARS-CoV-2/COVID-19 cases to the 
Sponsor and/or IRB/IEC according to the timeline and method outlined in the protocol. In 
addition, the Investigator agrees to submit annual reports to the study site IRB/IEC as 
appropriate. 
10.7 
Investigator’s Final Report 
Upon completion of the study, the Investigator, where applicable, should inform the institution; 
the Investigator/institution should provide the IRB/IEC with a summary of the study’s outcome 
and the Sponsor and regulatory authority(ies) with any reports required. 
10.8 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the study vaccine(s). These documents should be retained for a longer 
period, however, if required by the applicable regulatory requirements or by an agreement with 
the Sponsor. It is the responsibility of the Sponsor to inform the Investigator/institution as to 
when these documents no longer need to be retained. No records may be destroyed or transferred 
to another location or party without written notification to the Sponsor. 

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10.9 
Publications and Results Disclosures 
After completion of the study, the data may be considered for reporting at a scientific meeting or 
for publication in a scientific journal. In these cases, the Sponsor will be responsible for these 
activities and will work with the Investigators to determine how the manuscript is written and 
edited, the number and order of authors, the publication to which it will be submitted, and other 
related issues. The Sponsor has final approval authority over all such issues. 
Data are the property of the Sponsor and cannot be published without prior authorization from 
the Sponsor, but data and publication thereof will not be unduly withheld. 

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11 
STUDY MANAGEMENT 
The study administrative structure will include a blinded SRC, CRO, third-party vendors, and 
laboratories. 
11.1 
Monitoring 
11.1.1 
Monitoring of the Study 
This study will be monitored according to an approved monitoring plan based on the objectives, 
purpose, design, and complexity of the study. Site monitoring is conducted to ensure that the 
rights of human participants are protected, that the study is implemented in accordance with the 
protocol and/or other operating procedures, and that the study uses high-quality data collection 
processes. The monitor will evaluate study processes based on ICH E6(R2) and all applicable 
regulatory guidelines. The Investigator will allocate adequate time for all monitoring visits and 
between visits to facilitate the requirements of the study and study timelines. The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is given 
direct access to all study-related documents and study-related facilities (e.g., pharmacy and 
diagnostic laboratory), phone, fax, and internet and has adequate space to conduct the monitoring 
visit (if the monitoring visit is conducted in person). If the COVID-19 outbreak does not allow 
direct access to the site by the monitor, the Investigator will make every effort to provide access 
to source documents in a remote fashion. This includes anticipation of medical release forms to 
be signed by the participant at the time of study enrollment. 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all study records. In the 
event of an audit, the Investigator agrees to allow the Sponsor, representatives of the Sponsor, or 
a regulatory agency access to all study records. 
The Investigator should promptly notify the Sponsor and CRO of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the Sponsor. 
11.1.2 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all study records. In the 
event of an audit, the Investigator agrees to allow the Sponsor, representatives of the Sponsor, or 
a regulatory agency access to all study records. 
The Investigator should promptly notify the Sponsor and the CRO of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
Sponsor. 
11.2 
Management of Protocol Amendments and Deviations 
11.2.1 
 Modification of the Protocol 
Any changes in the required procedures defined in this protocol, except those necessary to 
remove an apparent, immediate hazard to the participant, must be reviewed and approved by the 
Sponsor or designee. Amendments to the protocol (including emergency changes) must be 

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submitted in writing to the Investigator’s IRB/IEC, along with any applicable changes to the ICF, 
for approval before participants can be enrolled into an amended protocol. 
11.2.2 
 Protocol Deviations 
A deviation from the protocol is an unintended or unanticipated departure from the procedures or 
processes approved by the Sponsor and the IRB/IEC and agreed to by the Investigator. A 
significant deviation occurs when there is nonadherence to the protocol or to local regulations or 
ICH GCP guidelines that could potentially result in a significant additional risk to the participant 
or impact the integrity of study data. 
The Investigator or designee must document and explain in the participant’s source 
documentation any deviation from the approved protocol. The Investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard/safety risk to study 
participants without prior IRB/IEC approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB/IEC for review and approval, to the Sponsor for agreement, and 
to the regulatory authorities, where required. 
In order to keep deviations from the protocol to a minimum, the Investigator and relevant site 
personnel will be trained in all aspects of study conduct by the Sponsor/Sponsor representative. 
This training will occur either as part of the Investigator meeting or site initiation. Ongoing 
training may also be performed throughout the study during routine site monitoring activities. 
As this study is planned for execution during a global health emergency (COVID-19 pandemic), 
there may be local restrictions that prevent or modify the performance of certain study-related 
procedures (e.g., clinic visits, blood sampling). For protocol deviations attributed to 
COVID-19 interruptions, relevant details leading to the protocol deviation will be captured in the 
source documents and EDC system in accordance with FDA guidance (FDA 2020a). 
11.3 
End of Study 
The EOS is defined as the date on which the last participant completes the last visit (includes 
Follow-up Visit). 
11.4 
 Early Study Termination 
Although Arcturus Therapeutics, Inc. has every intention of completing the study, Arcturus 
Therapeutics, Inc. reserves the right to discontinue the study at any time for clinical or 
administrative reasons. 
If the study is prematurely terminated or suspended, the Sponsor or Investigator shall promptly 
inform the Investigators, the IRBs/IECs, the regulatory authorities, and any CROs 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. 
11.5 
 Final Report 
Whether the study is completed or prematurely terminated, the Sponsor will ensure that the final 
data are summarized and provided to the regulatory agency(ies) as required by the applicable 

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regulatory requirement(s). The Sponsor will also ensure that any CSRs in marketing applications 
(as applicable) meet the standards of the ICH harmonised tripartite guideline E3: Structure and 
content of CSRs.  
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the CSR. The Investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results. 

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12 
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19): challenges and recommendations. Lancet Respir Med 2020; published online 06 April. 
https://doi.org/10.1016/S2213-2600(20)30161-2. 
Reuters 2021a 
Reuters: Russia approves its third COVID-19 vaccine, CoviVac. Published 19 Feb 2021: 
https://www.reuters.com/article/us-health-coronavirus-russia-vaccine-idUSKBN2AK07H. 
Accessed 22 March 2021. 
Reuters 2021b 
Reuters: China approves two more domestic COVID-19 vaccines for public use. Published 25 
February 2021. https://www.reuters.com/article/us-health-coronavirus-china-vaccine-
idUSKBN2AP1MW. Accessed 22 March 2021. 
Richardson 2020 
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, comorbidities, and 
outcomes among 5700 patients hospitalized with COVID-19 in the New York city area. JAMA. 
2020:323(20):2052-2059. https://doi.org/10.1001/jama.2020.6775. 
Rupp 2015 
Rupp, JC, Sokoloski, KJ, Gebhart, NN, Hardy, R.W. Alphavirus RNA synthesis and 
non-structural protein functions. J. Gen. Virol. 2015(96)2483-2500. 
Sahin 2020 
Sahin U, Muik A, Derhovanessian E, et al. Concurrent human antibody and TH1 type T-cell 
responses elicited by a COVID-19 RNA vaccine. medRxiv 2020; doi: 
https://doi.org/10.1101/2020.07.17.20140533. 
Sexson Tejtel 2021 
Sexson Tejtel SK, Munoz FM, Al-Ammouri I, et al. Myocarditis and pericarditis: case definition 
and guidelines for data collection, analysis, and presentation of immunization safety data. 2021. 

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https://brightoncollaboration.us/wp-content/uploads/2021/11/Myocarditis-and-Pericarditis-
manuscript_validated.pdf. Accessed 11 August 2022.  
Tortorici 2019 
Tortorici MA and Vessler D. Structural insights into coronavirus entry. Adv Virus Res. 
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Turkmenistan Today 2021 
Turkmenistan Today: Turkmenistan registers vaccines for the prevention of infectious diseases. 
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prevention-infectious-diseases. Accessed 22 March 2021. 
Van Doremalen 2020 
Van Doremalen N, Lambe T, Spencer A, et al. ChAdOx1 nCoV-19 vaccine prevents SARS-
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020-2608-y. 
Vogel 2020 
Vogel AB, Kanevsky I, Che Y, et al. A prefusion SARS-CoV-2 spike RNA vaccine is highly 
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ttps://www.biorxiv.org/content/10.1101/2020.09.08.280818v1.full.pdf.  
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Walsh, EE, Frenck R, Ann R. Falsey AR, et al. RNA-Based COVID-19 Vaccine BNT162b2 
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13 
APPENDICES 
 

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APPENDIX 1 SCHEDULE OF ASSESSMENTS - COHORT A (INCLUDING A1 AND A2) 
Visit Type: 
Screening Vaccination 
Visit 
Post Vax 
Day 4/32 
Visit 
Post Vax 
Day 8/36 
Visit 
Post Vax 
Day 15/43 
Visit 
Post Vax 
Day 57 
Visit 
Post Vax 
Day 
119/209/299 
Visit  
Unscheduled 
Visit 
ET 
Visit 
Final 
Visit 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica, b 
Clinica Clinica 
Study Day: 
-28 to -1  
1, 29 
4, 32 
8, 36 
15, 43 
 57 
119, 209, 
299  
N/A 
N/A 
394c 
Visit Window (days): 
0 
+1 (Day 29 
Only) 
+1 
+1 
+1 
±3 
±7 
N/A 
N/A 
+14 
Informed consent 
X 
  
Weight/height 
X 
  
Review of 
inclusion/exclusion criteria 
X 
  
Pregnancy testc 
X 
X 
  
Screening visit blood 
samplingd 
X 
  
Physical examinatione 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs and body 
temperaturef 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
  
Review for COVID-19 
symptoms and exposureg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for safety testingh 
X 
X 
X 
X 
X 
  

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Visit Type: 
Screening Vaccination 
Visit 
Post Vax 
Day 4/32 
Visit 
Post Vax 
Day 8/36 
Visit 
Post Vax 
Day 15/43 
Visit 
Post Vax 
Day 57 
Visit 
Post Vax 
Day 
119/209/299 
Visit  
Unscheduled 
Visit 
ET 
Visit 
Final 
Visit 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica, b 
Clinica Clinica 
Study Day: 
-28 to -1  
1, 29 
4, 32 
8, 36 
15, 43 
 57 
119, 209, 
299  
N/A 
N/A 
394c 
Visit Window (days): 
0 
+1 (Day 29 
Only) 
+1 
+1 
+1 
±3 
±7 
N/A 
N/A 
+14 
Study vaccine administrationi 
 
X 
 
 
 
 
 
 
 
  
Post-vaccination observationj 
 
X 
 
 
 
 
 
 
 
  
Blood sampling for 
immunogenicity antibody 
testingk 
X 
X 
X 
X 
X 
X 
Blood sampling for T-cell 
responsesl 
 
X 
 
 
X 
X 
X  
(Day 209 
only) 
 
X 
X 
Archival of serum samplem 
 
X 
 
 
X 
X 
X 
 
X 
X 
Archival of PBMC samplen 
 
X 
 
 
X 
X 
X  
(Day 209 
only) 
 
X 
X 
Sample for SARS-CoV-2o 
X 
  
Pulse oximetry 
X 
  
Adverse eventsp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Visit Type: 
Screening Vaccination 
Visit 
Post Vax 
Day 4/32 
Visit 
Post Vax 
Day 8/36 
Visit 
Post Vax 
Day 15/43 
Visit 
Post Vax 
Day 57 
Visit 
Post Vax 
Day 
119/209/299 
Visit  
Unscheduled 
Visit 
ET 
Visit 
Final 
Visit 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica, b 
Clinica Clinica 
Study Day: 
-28 to -1  
1, 29 
4, 32 
8, 36 
15, 43 
 57 
119, 209, 
299  
N/A 
N/A 
394c 
Visit Window (days): 
0 
+1 (Day 29 
Only) 
+1 
+1 
+1 
±3 
±7 
N/A 
N/A 
+14 
Concomitant medication, 
vaccinations, and procedure 
collectionq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary compliance checkr 
X 
X 
  
Counseling about long-term 
follow-up for SARS-CoV-2 
infections 
 
 
 
 
 
 
 
 
X 
 
Abbreviations: AE=adverse event; COVID-19=coronavirus disease 2019; ET=early termination; MAAE=medically attended adverse event; N/A=not applicable; 
PBMC= peripheral blood mononuclear cells; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome-coronavirus-2 ; 
vax=vaccination. 
a 
Visits will be performed in person unless the participant is otherwise directed to remain at home or be seen at a hospital. 
b 
Unscheduled visits include visits for specific safety issues and/or evaluation of possible COVID-19. These visits will ideally be performed in person; 
however, if local restrictions (e.g., lockdown) prevent this, they may be performed by telemedicine/telephone visit or home visit. Required procedures at 
these visits include AE and concomitant medication, vaccinations, and procedure collection. For participants evaluated for COVID-19, samples should be 
collected for SARS-CoV-2 testing. Should the visit occur in person, the visit should also include evaluation of vital signs, body temperature, pulse oximetry 
(if feasible), and symptom-directed physical examination.  
c 
Pregnancy testing will be performed on women who are not surgically sterile or postmenopausal. Pregnancy testing by urine dipstick is acceptable. 
Pregnancy testing will be performed and evaluated prior to each study vaccine administration. 
d 
Refer to Appendix 3 for a complete list of tests to be performed at Screening. 
e 
A complete physical examination will be performed at Screening, Day 1, Day 29, and Final Visit (or ET); a symptom-directed examination (if any 
symptoms) will be performed at other time points as indicated to assess changes from Day 1. Refer to Section 6.1.1 for details. 
f 
Blood pressure, heart rate, respiratory rate, and body temperature will be measured. 

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g 
A review of COVID-19 symptoms and risks will include a scripted interview of the participant for risks of recent exposure to COVID-19 and for symptoms 
of COVID-19. If symptoms or risk of COVID-19 is confirmed, testing for SARS-CoV-2 should be performed. If this is identified during the 
telemedicine/telephone visit with the participant, an unscheduled visit should be arranged.  
h 
Blood samples will be taken to perform hematology and chemistry panel. See Appendix 3 for a complete list of tests to be performed. 
i 
The study vaccine will be administered by intramuscular injection into the lateral aspect of the deltoid muscle of the nondominant arm, where possible. The 
study vaccine will be administered in an observer-blind fashion.  
j 
Vaccinated participants will be observed at the site for at least 30 minutes following study vaccine administration and until clinically stable.  After each 
study vaccine administration, vital signs should be checked, and repeat vital signs should be taken if clinically indicated. 
k 
Blood samples will be taken for antibody immunity testing at each time point noted; additional tube(s) of blood will be drawn at Day 29 and Day 57 for 
potential use in non-clinical passive transfer studies. 
l 
Blood samples will be taken for assessment of cell-mediated immunity testing at each time point noted.  
m 
Stored at -70°C for follow-up immunological assessments or exploration of laboratory findings and/or adverse events.  
n 
Stored at -70°C for follow-up immunological assessments or exploration of laboratory findings. 
o 
Use of provided SARS-CoV-2 test kit to be sent to a designated laboratory is strongly preferred. Approved alternate measures of virological confirmation of 
SARS-CoV-2 may be performed if it is not feasible to use provided kits.  
p 
Solicited AEs will be collected by paper Diary Cards for 7 days after each study vaccination for all participants. All unsolicited AEs will be collected 
through Screening and 28 days after each vaccination and if associated with an unscheduled visit. SAEs, MAAEs, and AEs leading to discontinuation of the 
study vaccine/study withdrawal are to be collected through the end of study participation.  
q 
Concomitant medications and procedures are to be collected from Screening through Day 28 following last vaccination and if associated with an 
unscheduled visit. Concomitant medications and procedures associated with SARS-CoV-2 infection/COVID-19 disease, SAEs, MAAEs and AEs leading to 
discontinuation of the study vaccine/study withdrawal are to be collected through to the end of study participation. Concomitant vaccinations are to be 
collected as early as 28 days prior to receipt of the first dose of study vaccine and through the end of study participation. 
r 
A compliance check is performed by site staff review of the paper Diary Card to confirm that the participant is entering the requested responses.  
s 
Participants who terminate from the study before completion will be told to inform the Investigator if they develop symptoms compatible with COVID-19 or 
a confirmed diagnosis of SARS-CoV-2 infection within 12 months after the last dose of the study vaccine. 
 

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APPENDIX 2 SCHEDULE OF ASSESSMENTS - COHORT B 
Visit Type: 
Screening Vaccination 
Visit 
Post Vax 
Day 4 
Visit 
Post Vax 
Day 8 
Visit 
Post Vax 
Day 15 
Visit 
Post Vax 
Day 29 
Visit 
Post Vax Day 
91, 181, 271 
Visit  
Unscheduled 
Visit 
ET 
Visit 
Final 
Visit 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica, b 
Clinica Clinica 
Study Day: 
-28 to -1  
1 
4 
8 
15 
29 
91, 181, 271 
N/A 
N/A 
366c 
Visit Window (days): 
0 
0 
0 
0 
+1 
+1 
±7 
N/A 
N/A 
+14 
Informed consent 
X 
 
 
 
 
 
 
 
 
Weight/height 
X 
 
 
 
 
 
 
 
 
Review of 
inclusion/exclusion criteria 
X 
Pregnancy testc 
X 
X 
Screening visit blood 
samplingd  
X 
Physical examinatione 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs and body 
temperaturef 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
Review for COVID-19 
symptoms and risksg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood safety testingh 
X 
X 
X 
X 
X 
Study vaccine 
administrationi 
X 

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Visit Type: 
Screening Vaccination 
Visit 
Post Vax 
Day 4 
Visit 
Post Vax 
Day 8 
Visit 
Post Vax 
Day 15 
Visit 
Post Vax 
Day 29 
Visit 
Post Vax Day 
91, 181, 271 
Visit  
Unscheduled 
Visit 
ET 
Visit 
Final 
Visit 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica 
Clinica, b 
Clinica Clinica 
Study Day: 
-28 to -1  
1 
4 
8 
15 
29 
91, 181, 271 
N/A 
N/A 
366c 
Visit Window (days): 
0 
0 
0 
0 
+1 
+1 
±7 
N/A 
N/A 
+14 
Post-vaccination 
observationj 
X 
Blood sampling for 
immunogenicity testingk 
 
X 
 
 
X 
X 
X 
 
X 
X 
Blood sampling for T-cell 
responsesl 
 
X 
 
 
X 
X 
X (Day 181 
only) 
 
X 
X 
Archival of serum samplem  
X 
 
 
X 
X 
X 
 
X 
X 
Archival of PBMC 
samplen 
 
X 
 
 
X 
X 
X (Day 181 
only 
 
X 
X 
Sample for SARS-CoV-2 o  
 
 
 
 
 
X 
 
 
Pulse oximetry 
 
 
 
 
 
 
X 
 
 
Adverse eventsp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
and procedure collectionq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary compliance checkr 
 
 
X 
X 
 
 
 
 
 
Counseling about long-
term follow-up for 
SARS-CoV-2 infection s 
 
 
 
 
 
 
 
X 
 

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Abbreviations: AE=adverse event; COVID-19=coronavirus disease 2019; ET=early termination; MAAE=medically attended adverse event; N/A=not applicable; 
PBMC= peripheral blood mononuclear cells; SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome-coronavirus 2. 
a 
Visits will be performed in person unless the participant is otherwise directed to remain at home or be seen at a hospital. 
b 
Unscheduled visits include visits for specific safety issues and/or evaluation of possible COVID-19. These visits will ideally be performed in person; 
however, if local restrictions (e.g., lockdown) prevent this, they may be performed by telemedicine/telephone visit or home visit. Required procedures at 
these visits include AE and concomitant medication, vaccinations, and procedure collection. For participants evaluated for COVID-19, samples should be 
collected for SARS-CoV-2 testing. Should the visit occur in person, the visit should also include evaluation of vital signs, body temperature, pulse oximetry 
(if feasible), and symptom-directed physical examination.  
c 
Pregnancy testing will be performed on women who are not surgically sterile or postmenopausal. Pregnancy testing by urine dipstick is acceptable. 
Pregnancy testing will be performed and evaluated prior to each study vaccine administration. 
d 
Refer to Appendix 3 for a complete list of tests to be performed at Screening.  
e 
A complete physical examination will be performed at Screening, Day 1, and Final Visit (or ET); symptom-directed examination (if any symptoms) will be 
performed at other time points as indicated to assess changes from Screening. Refer to Section 6.1.1 for details. 
f 
Blood pressure, heart rate, respiratory rate, and body temperature will be measured. 
g 
A review of COVID-19 symptoms and risks will include a scripted interview of the participant for risks of recent exposure to COVID-19 and for symptoms 
of COVID-19. If symptoms or risk of COVID-19 is confirmed, testing for SARS-CoV-2 should be performed. If this is identified during the 
telemedicine/telephone visit with the participant, an unscheduled visit should be arranged.  
h 
Blood samples will be taken to perform hematology and chemistry panel. See Appendix 3 for complete list of tests to be performed. 
i 
The study vaccine will be administered by intramuscular injection into the lateral aspect of the deltoid muscle of the nondominant arm, where possible. The 
study vaccine will be administered in an observer-blind fashion.  
j 
Vaccinated participants will be observed at the site for at least 30 minutes following study vaccine administration and until clinically stable. After each study  
vaccine administration, vital signs should be checked, and repeat vital signs should be taken if clinically indicated. 
k 
Blood samples will be taken for antibody immunity testing at each time point noted; additional tube(s) of blood will be drawn at Day 29 for potential use in 
non-clinical passive transfer studies. 
l 
Blood samples will be taken for cell-mediated immunity testing at each time point noted.  
m 
Stored at -70°C for follow-up immunological assessments or exploration of laboratory findings and/or adverse events.  
n 
Stored at -70°C for follow-up immunological assessments or exploration of laboratory findings.  
o 
Use of provided SARS-CoV-2 test kit to be sent to a designated laboratory is strongly preferred. Approved alternate measures of virological confirmation of 
SARS-CoV-2 may be performed if it is not feasible to use provided kits.  
p 
Solicited AEs will be collected by paper Diary Cards for 7 days after study vaccination for all participants. All unsolicited AEs will be collected through 
Screening and 28 days after vaccination and if associated with an unscheduled visit. SAEs. MAAEs and AEs leading to discontinuation of the study 
vaccine/study withdrawal are to be collected through end of study participation.  
q 
Concomitant medications and procedures are to be collected from Screening through Day 28 following last vaccination and if associated with an 
unscheduled visit. Concomitant medications and procedures associated with SARS-CoV-2 infection/COVID-19 disease, SAEs, MAAEs and AEs leading to 
discontinuation of the study vaccine/study withdrawal are to be collected through to the end of study participation. Concomitant vaccinations are to be 
collected as early as 28 days prior to receipt of the first dose of study vaccine and through the end of study participation. 
r 
A compliance check is performed by site staff review of the paper Diary Card to confirm that the participant is entering the requested responses.  
s 
Participants who terminate from the study before completion will be told to inform the Investigator if they develop symptoms compatible with COVID-19 or 
a confirmed diagnosis of SARS-CoV-2 infection for 1 year after vaccination so that they can be adequately followed up.

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APPENDIX 3 CLINICAL LABORATORY TESTS 
Safety Laboratory Assessments: 
Performed at Screening and at Day 1, Day 4, Day 
8, Day 29 (all cohorts), Day 32, Day 36, Day 57 
(Cohort A only) 
Screening Tests for 
Eligibility 
(Performed at 
Screening only) 
Immunogenicity 
Assessments (As per 
Schedule of Assessment 
for Cohort A and 
Cohort B) 
Clinical Chemistry 
Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Glucose 
(random) 
• 
BUN 
• 
Creatinine 
• 
Total bilirubin 
• 
Direct 
(conjugated) 
bilirubin 
• 
Indirect 
(unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline 
phosphatase 
• 
Creatinine 
kinase 
• 
GGT 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH  
• 
MCHC 
• 
Platelets 
• 
White blood 
cells  
• 
WBC 
differential (% 
and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Hepatitis B 
surface antigen 
• 
Hepatitis C 
antibody 
• 
HIV antibody 
• 
FSH (women 
only, as 
clinically 
warranted to 
clarify 
menopausal 
status) 
• 
Serum/urine 
βhCG 
• 
HbA1c (if 
warranted for 
individuals with 
diabetes 
mellitus 
Type 2) 
• 
SARS-CoV-2 
nucleocapsid 
binding 
antibody (Sub-
cohort A1 - 
South Africa 
and US 
participants 
only; Sub-
cohort A2 – All 
countries) 
• 
SARS-CoV-2 
neutralizing 
antibody 
concentration by 
pseudoviral 
microneutralization 
assay  
• 
Anti-S, N-, and 
RBD protein IgG 
by MSD multiplex 
assay 
• 
ELISpot (Oxford 
Immunotec T-spot)  
• 
Intracellular 
cytokine staining 
(ICS) 
• 
Fc effector 
function 
• 
Additional 
exploratory 
immunogenicity 
tests will be 
specified in the 
SAP, if performed. 
Virology (Performed at 
Unscheduled Visit only) 
• 
SARS-CoV-2 
detection by 
RT-PCR or 
rapid antigen 
test 

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Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; βhCG=beta human chorionic 
gonadotropin; BUN=blood urea nitrogen; ELISpot=enzyme-linked immune absorbent spot; 
FSH=follicle-stimulating hormone; GGT=gamma-glutamyl transferase; HbA1c=hemoglobin A1C; 
IgG=Immunoglobulin G; MCV=Mean Corpuscular Volume; MCH=Mean corpuscular hemoglobin; 
RBD=receptor-binding domain; RT-PCR=Reverse transcriptase polymerase chain reaction; SAP=Statistical 
analysis plan; SARS-CoV-2=severe acute respiratory syndrome-coronavirus 2. 
 

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APPENDIX 4 CONTRACEPTIVE GUIDANCE 
Male Participant Reproductive Inclusion Criteria 
Male participants are eligible to participate if they agree to the following requirements during the 
intervention period and for at least 60 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study intervention(s): 
• Refrain from donating sperm. 
PLUS, either: 
• Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to 
remain abstinent. 
OR 
• Must agree to use a male condom when engaging in any activity that allows for passage 
of ejaculate to another person. 
• In addition to male condom use, a highly effective method of contraception may be 
considered in women of childbearing potential (WOCBP) partners of male participants (refer 
to the list of highly effective methods below). 
Female Participant Reproductive Inclusion Criteria 
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 
1 of the following conditions applies: 
• Is not a WOCBP (see definitions below). 
OR 
• Is a WOCBP and using an acceptable contraceptive method as described below during 
the intervention period (for a minimum of 60 days after the last dose of study intervention). 
The Investigator should evaluate the effectiveness of the contraceptive method in relationship 
to the first dose of study intervention. 
The Investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before the first dose of study intervention, additional evaluation should be considered, 
including FSH test. 
Women in the following categories are not considered WOCBP: 
• Premenopausal female with 1 of the following: 
− Documented hysterectomy. 
− Documented bilateral salpingectomy. 

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− Documented bilateral oophorectomy. 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Note: Documentation for any of the above categories can come from the site personnel’s review 
of the participant’s medical records, medical examination, or medical history interview. The 
method of documentation should be recorded in the participant’s medical record for the study. 
• Postmenopausal defined as follows: 
− A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
− A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or hormone replacement therapy (HRT). 
− A female participant 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. 
Contraception Methods Inclusion Criteria 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical studies. 
Acceptable and highly effective contraception methods include the following:  
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation. 
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
• Vasectomized partner: 
− Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
The spermatogenesis cycle is approximately 90 days. 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
− Injectable 
• Progestogen-only hormone contraception associated with inhibition of ovulation: 
− Oral 

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− Injectable 
• Double barrier methods: a combination of male condom with either cervical cap, 
diaphragm, or sponge with spermicide. 
• 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. 
The following methods of birth control are not regarded as highly reliable methods and are 
therefore discouraged as a single method only for contraception:  
• Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action. 
• Male or female condom with or without spermicide. 
• Cervical cap, diaphragm, or sponge with spermicide. 

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APPENDIX 5 TOXICITY GRADING SCALE SOLICITED ADVERSE EVENTS 
Solicited Local 
AEs 
Grade 0 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially 
Life 
Threatening) 
Injection Site 
Erythema *  
<2.5 cm 
2.5–5 cm  
5.1–10 cm  
>10 cm  
Emergency 
Room (ER) 
visit, 
hospitalization 
or necrosis or 
exfoliative 
dermatitis  
Injection Site 
Induration/Swellin
g ** 
<2.5 cm 
 
2.5–5 cm and 
does not 
interfere with 
activity  
5.1–10 cm or 
interferes with 
activity  
>10 cm or 
prevents 
daily activity  
ER visit or 
hospitalization 
or necrosis  
Injection Site Pain 
None 
No 
interference 
with activity  
Some interference 
with daily activity or 
leads to use of non-
narcotic pain 
reliever for >24 
hours 
Prevents 
daily activity 
or leads to 
use of 
narcotic pain 
reliever  
ER visit or 
hospitalization  
Injection Site 
Tenderness 
None 
Mild 
discomfort to 
touch  
Discomfort with 
movement  
Significant 
discomfort at 
rest  
ER visit or 
hospitalization  
Solicited Systemic 
AEs 
 
 
 
 
 
Fever (°C)*** 
(°F) *** 
<38.0 
<100.4 
38.0–38.4 
100.4–101.1 
38.5–38.9 
101.2–102.0 
39.0–40 
102.1–104 
>40 
>104 
Nausea/vomiting 
None 
No 
interference 
with activity 
or 1–2 
episodes/24 
hours  
Some interference 
with activity or 
>2 episodes/24 hour
s without seeking 
medical attention 
Prevents 
daily activity 
or requires 
outpatient IV 
hydration  
ER visit or 
hospitalization 
for 
hypotensive 
shock  
Diarrhea 
<2 loose 
stools/24 hours 
2–3 loose 
stools or 
<400 g/24 
hours 
4–5 stools or  
400–800 g/24 hours  
6 or more 
loose or 
watery stools 
or >800 g/24 
hours or 
requires 
outpatient IV 
hydration  
ER visit or 
hospitalization  
Headache 
None 
No 
interference 
with activity  
Some interference 
with daily activity or 
leads to use of non- 
narcotic pain 
reliever >24 hours  
Significant; 
prevents 
daily activity 
or leads to 
use of 
narcotic pain 
reliever 
ER visit or 
hospitalization  

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Solicited Local 
AEs 
Grade 0 
Grade 1 
(Mild) 
Grade 2 
(Moderate) 
Grade 3 
(Severe) 
Grade 4 
(Potentially 
Life 
Threatening) 
Fatigue  
None 
No 
interference 
with activity  
Some interference 
with activity  
Significant; 
prevents 
daily activity  
ER visit or 
hospitalization  
Myalgia  
None 
No 
interference 
with activity  
Some interference 
with activity  
Significant; 
prevents 
daily activity  
ER visit or 
hospitalization  
Arthralgia, chills, 
dizziness 
None 
No 
interference 
with activity  
Some interference 
with activity but 
does not require 
medical intervention 
Prevents 
daily activity 
and requires 
medical 
intervention 
ER visit or 
hospitalization  
Abbreviation: ER=emergency room 
* 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. 
*** If temperature taken orally, no recent hot or cold beverages or smoking. 
Adapted from Source: DHHS 2007. 
 
 

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APPENDIX 6 LIST OF EXCLUSIONARY AUTOIMMUNE DISEASES 
The following list details the autoimmune diseases listed by the American Autoimmune Related 
Disease Association (Autoimmune Association 2022). These autoimmune diseases represent 
exclusion criteria for the purpose of eligibility to participate in this study.  
• Achalasia  
• Addison’s disease  
• Adult Still's disease  
• Agammaglobulinemia  
• Alopecia areata  
• Amyloidosis  
• Ankylosing spondylitis  
• Anti-glomerular basement membrane / Anti-tubular basement membrane nephritis  
• Antiphospholipid syndrome  
• Autoimmune angioedema  
• Autoimmune dysautonomia  
• Autoimmune encephalitis  
• Autoimmune hepatitis  
• Autoimmune inner ear disease  
• Autoimmune myocarditis  
• Autoimmune oophoritis  
• Autoimmune orchitis  
• Autoimmune pancreatitis  
• Autoimmune retinopathy  
• Autoimmune urticaria  
• Axonal & neuronal neuropathy  
• Baló disease  
• Behcet’s disease  
• Benign mucosal pemphigoid  
• Bullous pemphigoid  
• Castleman disease  
• Celiac disease  
• Chagas disease  
• Chronic inflammatory demyelinating polyneuropathy  
• Chronic recurrent multifocal osteomyelitis  
• Churg-Strauss syndrome or Eosinophilic granulomatosis  
• Cicatricial pemphigoid  
• Cogan’s syndrome  
• Cold agglutinin disease  
• Complex regional pain syndrome 
• Congenital heart block  
• Coxsackie myocarditis  
• CREST syndrome  
• Crohn’s disease  

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• Dermatitis herpetiformis  
• Dermatomyositis  
• Devic’s disease  
• Discoid lupus  
• Dressler’s syndrome  
• Endometriosis  
• Eosinophilic esophagitis  
• Eosinophilic fasciitis  
• Erythema nodosum  
• Essential mixed cryoglobulinemia  
• Evans syndrome  
• Fibromyalgia  
• Fibrosing alveolitis  
• Giant cell arteritis (temporal arteritis)  
• Giant cell myocarditis  
• Glomerulonephritis  
• Goodpasture’s syndrome  
• Granulomatosis with Polyangiitis  
• Graves’ disease  
• Guillain-Barre syndrome  
• Hashimoto’s thyroiditis  
• Hemolytic anemia  
• Henoch-Schonlein purpura  
• Herpes gestationis or pemphigoid gestationis  
• Hidradenitis suppurativa (Acne inversa)  
• Hypogammaglobulinemia  
• IgA nephropathy  
• IgG4-related sclerosing disease  
• Immune thrombocytopenic purpura  
• Inclusion body myositis  
• Interstitial cystitis  
• Juvenile arthritis  
• Juvenile diabetes (Type 1 diabetes)  
• Juvenile myositis  
• Kawasaki disease  
• Lambert-Eaton syndrome  
• Lichen planus  
• Lichen sclerosus  
• Ligneous conjunctivitis  
• Linear IgA disease  
• Lupus  
• Lyme disease chronic  
• Meniere’s disease  

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• Microscopic polyangiitis  
• Mixed connective tissue disease  
• Mucha-Habermann disease  
• Multifocal motor neuropathy  
• Multiple sclerosis  
• Myasthenia gravis  
• Myelin oligodendrocyte glycoprotein antibody disorder 
• Myositis  
• Narcolepsy  
• Neonatal lupus  
• Neuromyelitis optica  
• Neutropenia  
• Ocular cicatricial pemphigoid  
• Optic neuritis  
• Palindromic rheumatism  
• Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections 
• Paraneoplastic cerebellar degeneration  
• Paroxysmal nocturnal hemoglobinuria  
• Parry-Romberg syndrome  
• Pars planitis (peripheral uveitis)  
• Parsonage-Turner syndrome  
• Pemphigus  
• Peripheral neuropathy  
• Perivenous encephalomyelitis  
• Pernicious anemia  
• POEMS syndrome  
• Polyarteritis nodosa  
• Polyglandular syndromes type 1, 2, 3  
• Polymyalgia rheumatica  
• Polymyositis  
• Postmyocardial infarction syndrome  
• Postpericardiotomy syndrome  
• Primary biliary cholangitis  
• Primary sclerosing cholangitis  
• Progesterone dermatitis  
• Progressive hemifacial atrophy 
• Psoriasis  
• Psoriatic arthritis  
• Pure red cell aplasia  
• Pyoderma gangrenosum  
• Raynaud’s phenomenon  
• Reactive arthritis  
• Relapsing polychondritis  

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• Restless legs syndrome  
• Retroperitoneal fibrosis  
• Rheumatic fever  
• Rheumatoid arthritis  
• Sarcoidosis  
• Schmidt syndrome or Autoimmune polyendocrine syndrome type II 
• Scleritis  
• Scleroderma  
• Sjögren’s disease  
• Stiff person syndrome  
• Susac’s syndrome  
• Sympathetic ophthalmia  
• Takayasu’s arteritis  
• Temporal arteritis / giant cell arteritis  
• Thrombocytopenic purpura  
• Thrombotic thrombocytopenic purpura 
• Thyroid eye disease  
• Tolosa-Hunt syndrome  
• Transverse myelitis  
• Type 1 diabetes  
• Ulcerative colitis  
• Undifferentiated connective tissue disease  
• Uveitis  
• Vasculitis  
• Vitiligo  
• Vogt-Koyanagi-Harada disease 
• Warm autoimmune hemolytic anemia 
 

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APPENDIX 7 CASE DEFINITIONS FOR COVID-19 
Primary Case Definition (Based on FDA recommendation [DHHS 2020]) 
Case Definition  
Laboratory Finding* 
Clinical Status 
Symptoms 
Other Clinical Parameters 
Uninfected 
No positive SARS-CoV-
2 test 
None 
None relevant 
Asymptomatic SARS-
CoV-2 Infection 
Positive SARS-CoV-2 
test 
None 
None relevant 
Protocol-defined 
COVID-19 
Positive SARS-CoV-2 
test 
At least one of the following that is 
a NEW or WORSENING finding:  
Fever or chills 
Cough 
Shortness of breath or difficulty 
breathing 
Fatigue 
Muscle or body aches 
Headache 
New loss of taste or smell 
Sore throat 
Congestion or runny nose 
Nausea or vomiting 
Diarrhea 
None relevant 
Atypical COVID-19 
Positive SARS-CoV-2 
test 
Clinical findings suggestive of 
COVID-19 but not included in the 
row above 
None relevant 
Severe COVID-19 
Positive SARS-CoV-2 
test 
As above for protocol-defined 
COVID-19 
Any of the following: 
• 
Clinical signs at rest indicative of severe systemic 
illness: 
- 
Respiratory rate ≥30 per minute, 
- 
Heart rate ≥125 per minute, 
- 
SpO2 ≤93% on room air at sea level or PO2/FiO2 
<300 mm Hg 

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Case Definition  
Laboratory Finding* 
Clinical Status 
Symptoms 
Other Clinical Parameters 
• 
Respiratory failure (defined as needing high flow 
oxygen, noninvasive ventilation, mechanical 
ventilation or ECMO) 
• 
Evidence of shock: 
- 
SBP <90 mm Hg, or 
- 
DBP <60 mm Hg,  
- 
or requiring vasopressors 
• 
Significant acute renal, hepatic, or neurologic 
dysfunction 
• 
Admission to an ICU 
• 
Death 
Abbreviations: COVID-19=coronavirus disease 2019; DBP=diastolic blood pressure; ECMO=extracorporeal membrane oxygenation; FiO2=fraction of 
inspired oxygen; ICU=intensive care unit; pO2=partial pressure of oxygen; SARS-CoV-2=severe acute respiratory syndrome-coronavirus-2; SBP=systolic 
blood pressure; SpO2=oxygen saturation. 
Alternate Case Definition for Grading of Severity of SARS-CoV-2 Infection/COVID-19 (Based on World Health Organization 
recommendation [WHO 2020c]) 
Case Definition 
Lab Finding* 
Clinical Status 
Other Clinical Parameters 
Score 
Uninfected 
No positive SARS-CoV-2 test 
N/A 
N/A 
0 
Mild Disease 
Positive SARS-CoV-2 test 
Ambulatory 
Asymptomatic 
1 
Symptomatic; independent 
2 
Symptomatic; assistance needed 
3 
Moderate Disease 
Positive SARS-CoV-2 test 
Hospitalized 
No oxygen therapy  
NOTE: If hospitalized for isolation only, 
record status as for ambulatory patient 
4 
Oxygen by mask or nasal prongs 
5 
Severe Disease 
Positive SARS-CoV-2 test 
Hospitalized 
Oxygen by NIV or high flow 
6 
Intubation and mechanical ventilation,  
pO2/FiO2≥150 or  
SpO2/FiO2≥200 
7 

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Case Definition 
Lab Finding* 
Clinical Status 
Other Clinical Parameters 
Score 
Mechanical ventilation, 
pO2/FiO2<150 or  
SpO2/FiO2<200 or 
vasopressors 
8 
Mechanical ventilation, 
pO2/FiO2<150 and vasopressors, dialysis 
or ECMO 
9 
Dead 
Positive SARS-CoV-2 test 
Dead 
N/A 
10 
Abbreviations: ECMO=extracorporeal membrane oxygenation; FiO2=fraction of inspired oxygen; N/A=not applicable; NIV=noninvasive ventilation; 
pO2=partial pressure of oxygen; SARS-CoV-2=severe acute respiratory syndrome-coronavirus-2; SpO2=oxygen saturation. 
Laboratory Confirmation of SARS-CoV-2 Infection 
SARS-CoV-2 viral infection as measured by either reverse transcriptase-polymerase chain reaction (RT-PCR) test or other equivalent 
nucleic acid amplification–based test (i.e., NAAT). Results from the central laboratory (preferred) or from local laboratory will be 
used; however, if local tests are used, the laboratory test will be considered acceptable if it was obtained using: 
• A Food and Drug Administration-cleared assay 
• An assay performed in a laboratory that is currently Clinical Laboratory Improvement Amendment (CLIA-certified 
• An assay performed by a laboratory accredited according to the International Organization for Standardization 
(ISO 15189 standard), OR 
• An assay accredited by a national or regional authority in the country concerned 
 

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APPENDIX 8 PROTOCOL AMENDMENTS 
Protocol Amendment 1 (Version 2.0, 16 July 2021): Summary of Changes 
Section Number and 
Name 
Description of Change 
Brief Rationale 
Throughout Protocol 
Corrected spelling and 
grammar; inserted previously 
missing definitions of 
acronyms and abbreviations at 
first use. 
Improve clarity. 
Title Page, Protocol 
Approval – Sponsor, 
Declaration of Investigator, 
Page Header 
Revised version and date of the 
protocol from 27 May 2021, 
Version 1.0 to 16 July 2021, 
Version 2.0. 
Updated version and date of 
protocol due to protocol 
amendment. 
Throughout Protocol: 
--Study Design 
--Target Population 
 --Number of Sites 
Included additional countries 
of South Africa and the US 
where sites may be added. 
Addition of sites in other 
countries to support enrollment 
of Cohorts A and B. 
Throughout Protocol: 
--Study Design 
 
Updated text to applicable 
health authorities rather than 
listing specific health authority 
from Singapore. 
Updated to refer to applicable 
health authorities due to option 
of additional sites in other 
countries. 
Throughout Protocol: 
--Study Design 
--Target Population 
Cohort B inclusion criteria 
updated (from 6 months to 5 
months) to those who have 
been previously vaccinated (5 
months or longer prior to 
enrollment) with the BNT162b 
(Comirnaty) SARS-Cov-2 
vaccine. 
To enable increased participant 
eligibility in the Cohort B 
population. 
Throughout Protocol: 
-- Synopsis 
--Study Design 
--Vital Signs and Body 
Temperature 
 --Schedule of Assessments 
Updated to separate vital signs 
and body temperature. 
Ensure consistency throughout 
protocol. 

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Section Number and 
Name 
Description of Change 
Brief Rationale 
Synopsis and Protocol 
Body Section 3.1.1: 
Rationale for Study Design 
South Africa and US 
mentioned in addition to 
Singapore in this section. 
Given the presence of study 
vaccination campaigns in 
Singapore, South Africa and 
the US, a study with all active 
vaccine arms was considered 
more appropriate than a 
placebo-controlled study. 
Section 1.7.1 (Table 1) 
Potential Risks 
Updated text for the mitigation 
measures for the 2 previously 
highlighted potential risks. 
To ensure consistency with the 
latest version of the IB (v5.0, 
07July2021). 
Section 4.1.2 Exclusion 
Criteria 
Added positive SARS-CoV-2 
nucleocapsid binding antibody 
test results at screening (in US 
and SA only) for Cohort A to 
the exclusion criteria. 
The study aims to evaluate 
vaccine responses in 
individuals with and without 
prior exposure to SARS-Cov-2 
antigens. As there has been 
high rates of circulation of 
SARS-CoV-2 infection in 
South Africa and the US and in 
order to reduce the risk that 
Cohort A has previously been 
exposed to SARS-Cov-2 
antigens through infection, the 
nucleocapsid test will be 
included at screening in these 
two countries. 
Section 5.7.1 Concomitant 
Therapy 
Updated from “first” to “each” 
to clarify that participants will 
be asked for 7 days after each 
vaccination in the paper diary 
card whether they have taken 
any antipyretic or analgesics. 
Correction of typographical 
error. 
Section 5.7.2 Prohibited 
Concomitant Vaccines and 
Concomitant Therapy 
Deleted repetitive text 
regarding recording of 
concomitant medications as it 
is already covered in the 
appropriate section 5.7.1 
(Concomitant Therapy). 
Removal of redundant text for 
this section.  

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Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 6.1.7 Diary Card 
Procedures 
Added text that data from the 
diary card must be transcribed 
verbatim into the electronic 
data capture system. 
Clarification to sites to ensure 
data is transcribed verbatim 
from the diary card. 
Section 6.3.1.2 Adverse 
Events 
Deleted text regarding when 
solicited events would be 
considered to be unsolicited.  
Text is covered in more detail 
in subsequent sections on 
solicited and unsolicited 
events. 
Section 6.3.1.2.6 Solicited 
Adverse Events 
Updated from “first” to “each” 
to clarify that solicited AEs 
will be collected from 
participants by Diary Cards for 
7 days following each vaccine. 
Clarification of existing text. 
Section 6.3.1.2.8 Eliciting 
and Documenting Adverse 
Events 
Additional clarification and 
examples of types of AEs from 
study data provided. 
Added additional clarification 
and examples of types of AEs 
that may be identified from 
study data. 
Section 7.4 Interim 
Analysis 
Clarified that additional 
cohorts will not exceed 
12 participants in each 
treatment group. 
Clarification of existing text. 
Section 7.5.3 Safety 
Analysis 
Additional clarification text 
provided regarding toxicity 
grading scale, criteria for 
unsolicited events and addition 
of toxicity grading scale 
reference. 
Clarification of existing text 
and addition of reference for 
toxicity grading scale. 
Section 12 References 
Updated Arcturus IB version 
to latest version (v5.0, 
07July2021). 
Updated IB reference to latest 
version. 
Appendix 1 Schedule of 
Assessments – Cohort A, 
Appendix 2 Schedule of 
Assessments – Cohort B 
Deleted redundant text “and/or 
adverse events” with regards to 
PBMC immunological 
assessments. 
Removal of redundant text. 

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Section Number and 
Name 
Description of Change 
Brief Rationale 
Appendix 3 Clinical 
Laboratory Tests 
Added SARS-CoV-2 
nucleocapsid binding antibody 
test to screening tests for 
eligibility for Cohort A 
participants (South Africa and 
US only). 
Given the higher rates of 
SARS-CoV-2 infection in 
South Africa and the US, 
nucleocapsid testing added at 
screening in these countries to 
exclude those with a positive 
test. 
Appendix 5 Toxicity 
Grading Scale Solicited 
Adverse Events 
Updated to include criteria for 
Grade 0 solicited adverse 
events. 
Grade 0 criteria added for 
completeness. 
 
Protocol Amendment 2 (Version 3.0, 10 March 2022): Summary of Changes 
Section Number and 
Name 
Description of Change 
Brief Rationale 
Throughout Protocol 
Corrected spelling and/or 
grammar 
Improve clarity. 
Throughout Protocol 
• Replaced “Wuhan strain” 
with “ancestral strain”. 
• Replaced “B.1.351 
variant strain” with “SARS-
CoV-2 variant strain” 
Improve clarity. 
• Title Page 
• Protocol Approval – 
Sponsor Signatory 
• Declaration of 
Investigator 
•  Page Headers 
Revised version and date of the 
protocol from 16July2021, 
Version 2.0 to10March2022, 
Version 3.0. 
Updated version and date of 
protocol due to protocol 
amendment. 
• Protocol Synopsis 
• List of Abbreviations 
• Table 2 Primary 
Objectives and Endpoints 
Replaced GMT to GMC in 
appropriate locations. 
Clarification of text. 
• Protocol Synopsis 
• Section 3.1 Study 
Design 
Replaced text regarding 
enrollment of up to 72 
additional participants 
following interim analysis with 
Updated to remove mention 
of specific numbers and 
enable appropriate cohort 
enrollment following 

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Section Number and 
Name 
Description of Change 
Brief Rationale 
“Based on the review of 
interim analysis data, the study 
may be amended to further 
explore LUNAR SARS-CoV-2 
vaccine development.” 
review of interim data. 
• Section 1.4 
Mechanism of Action 
• Section 1.5 Clinical 
Study Experiences with 
ARCT-165, ARCT-154, 
and ARCT-021 
• Section 1.6 Rationale 
for Dose Regimen 
Selection 
• Section 1.7.1 
Potential Risks 
• Section 12 References 
Updated reference to reflect the 
new IB version and date (IB 
Version 6.0 dated 10Jan2022). 
Reflect updated study 
documentation. 
• Protocol Synopsis 
• Section 3.1 Study 
Design 
• Figure 1 ARCT-165-
01 Study Schema 
• Section 3.1.1 
Rationale for Study 
Design 
• Section 6.2.1 Cohort 
A Visits 
• Appendix 1 Schedule 
of Assessments - Cohort 
A 
Updated to include Sub-cohort 
A1 and Sub-cohort A2 within 
Cohort A. 
Cohort A criteria expanded 
to include unvaccinated 
participants who are 
seropositive at screening, 
therefore Cohort A updated 
to include 2 Sub-cohorts A1 
and A2. 
• Protocol Synopsis 
• Protocol Body 
• Section 3.1.1 
Rationale for Study 
Design 
Rationale for update to include 
Sub-cohort A2 (unvaccinated 
participants who are 
seropositive at screening) 
added 
Important to study 
population of unvaccinated 
individuals who are 
seropositive given high 
prevalence of this 
population worldwide. 

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Protocol ARCT-165-01, Version 4.0 
22 August 2022 
109Confidential 
Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 1.5 Clinical Study 
Experience with ARCT-
165, ARCT-154 and 
ARCT-021 
Updated with information from 
the ARCT-021 and ARCT-
154-01 
Provide up-to date 
information on ongoing 
clinical studies ARCT-021-
04 and ARCT-154-01. 
• Table 1 Risk 
Minimization Measures 
Included in Clinical 
Studies of ARCT-021, 
ARCT-154 and ARCT-
165 
• Section 1.7.1 
Potential Risks 
Updated with additional risk 
minimization measures  
Inclusion of additional risk 
minimization measures for 
myocarditis/pericarditis and 
hypertension based on 
safety risks from other 
mRNA SARS-CoV-2 
vaccines and evolving 
blinded safety data 
respectively. 
Section 4.1.1 Inclusion 
Criteria 
Updated Inclusion Criteria for 
Sub-cohort A2 
Inclusion criteria for Sub-
cohort A2 to include a 
positive nucleocapsid test at 
screening. 
Section 4.1.2 Exclusion 
Criteria 
Updated Exclusion criteria to 
specify Sub-cohort A1 
Exclusion criteria for a 
negative nucleocapsid test 
at screening clarified for 
Sub-cohort A1. 
Section 4.1.2 Exclusion 
Criteria 
Deleted “as an adult” for 
exclusion criteria 11 b 
To ensure any participant 
with a prior history of 
myocarditis and/or 
pericarditis at any age is 
excluded. 
Section 4.1.3 Screen 
Failures 
Included “Screening vital 
sign assessments may be 
repeated twice if the first 
value is inconsistent with 
previously documented vital 
signs”. 
To incorporate current 
procedures from Protocol 
Administrative Amendment 
#3 within Protocol V3.0. 
Section 4.2.2.1 Stopping 
Rules for Adverse Events 
in Individual Participants 
Added myocarditis, pericarditis 
and hypertensive crisis as 
adverse events that would 
trigger stopping rules for 
individual participants 
Update of study risk 
minimization measures for 
myocarditis, pericarditis 
and hypertension  

Arcturus Therapeutics, Inc. 
 
Protocol ARCT-165-01, Version 4.0 
22 August 2022 
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Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 6.12 Vital Signs 
and Body Temperature 
Section 6.2.2.2 Vaccination 
Visit on Day 1 
Appendix 1 Schedule of 
Assessments – Cohort A 
Appendix 2 Schedule of 
Assessments – Cohort B 
Updated text to specify that 
after each study vaccine 
administration, vital signs 
should be checked, and repeat 
vital signs should be taken if 
clinically indicated. 
Ensure that post-
vaccination blood pressure 
measurements are 
performed given the signal 
of hypertension from study 
ARCT-154-01. 
Section 6.3.1.2.11 
Reporting Adverse Events 
Updated text for 
commencement of adverse 
event reporting. 
Correction of text to align 
with Section 6.3.1.2.8 
(Eliciting and Documenting 
Adverse Events) for 
assessment of adverse 
events from the time the 
participant signs the 
informed consent form 
(ICF). 
Section 6.7 Surveillance 
for SARS-CoV-2 Infection 
Included guidance for 
managing participants with 
suspected/confirmed COVID-
19. 
To incorporate current 
procedures from Protocol 
Administrative Amendment 
#3 within Protocol V3.0, as 
well as allowance for rapid 
antigen tests. 
Section 7.4 Interim 
Analysis 
Updated to clarify “self-
amplifying” and removal of 
text that additional cohorts will 
not exceed 12 participants in 
each treatment group. 
Addition of future study 
vaccines that are not self-
amplifying may be at doses 
greater than 5 µg. As Sub-
cohort A2 has greater than 
12 participants in treatment 
group, it is possible that 
future additional cohorts 
may warrant greater than 
12 participants in a 
treatment group. 
Appendix 1 Schedule of 
Assessments – Cohort A 
Expansion of visit windows for 
Day 1,4, 8, 29, 32 and 36 
visits.  
For logistical reasons, 
allows some flexibility for 
sites in arranging study 
visits around weekends. 

Arcturus Therapeutics, Inc. 
 
Protocol ARCT-165-01, Version 4.0 
22 August 2022 
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Section Number and 
Name 
Description of Change 
Brief Rationale 
Appendix 3 Clinical 
Laboratory Tests 
Clarification of screening tests 
for Sub-cohorts A1 and A2 and 
inclusion of intracellular 
cytokine staining (ICS) for 
immunogenicity assessments.  
Allowance of rapid antigen 
tests for unscheduled visits.  
Clarification of existing text 
and addition of test to 
immunogenicity 
assessments. Allowance of 
rapid antigen tests for 
unscheduled visits to reflect 
updates made in Section 
6.7. 
 
Protocol Amendment 3 (Version 4.0, 22 August 2022): Summary of Changes 
Section Number and 
Name 
Description of Change 
Brief Rationale 
Throughout Protocol 
Corrected spelling and/or 
grammar. 
Improve clarity. 
Section 1.7.1 Potential 
Risks 
Updated risk mitigations for 
myocarditis and 
pericarditis. 
Align risk mitigations with 
other changes implemented 
in the protocol. 
Section 4.2.4 Study-wide 
Pausing and Stopping 
Rules 
Added a stopping rule for 
myocarditis and/or 
pericarditis. 
Risk mitigation in cases of 
reported vaccine-related 
myocarditis and/or 
pericarditis events. 
Section 6.3.1.2.5 Adverse 
Event of Special Interest 
Myocarditis/pericarditis 
added as an AESI under 
Brighton Collaboration case 
definition. Clarification of 
requirements for reporting 
and follow-up of events was 
added. 
Risk mitigation in cases of 
reported vaccine-related 
myocarditis and/or 
pericarditis events and 
addition of reporting 
requirements. 
Section 6.7 Surveillance 
for SARS-CoV-2 Infection 
Specified assessment of 
causality and severity for 
COVID-19 cases should be 
aligned with other 
unsolicited adverse event 
reporting. 
Specified that oxygen 
saturation should be 
collected during daily check 
calls only if feasible. 
Clarification and alignment 
with administrative 
amendment. 

Arcturus Therapeutics, Inc. 
 
Protocol ARCT-165-01, Version 4.0 
22 August 2022 
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Section Number and 
Name 
Description of Change 
Brief Rationale 
Section 12 References 
The Brighton Collaboration 
case definition for 
pericarditis was added as a 
reference. 
Referenced in Section 
6.3.1.2.5. 
Appendix 6 List of 
Exclusionary Autoimmune 
Diseases 
Updated list of autoimmune 
diseases. 
Align with referenced 
webpage, which has been 
updated.