A Phase 1/2 Randomized, Active- Controlled, Observer-blind Trial to Assess the Safety and Immunogenicity of COVIVAC Vaccine Produced by IVAC in Adults ≥ 18 and ≥ 60 Years Old in Vietnam
Phase: PHASE2
Conditions: COVID-19
Sponsor: Institute of Vaccines and Medical Biologicals, Vietnam

 
 
 
 
 
A Phase 1/2 Randomized, Placebo-controlled (phase 1) and Active- 
controlled (phase 2), Observer-blind Trial to Assess the Safety and 
Immunogenicity of COVIVAC Vaccine produced by IVAC in 
Adults ≥ 18 and ≥ 60 years old in Vietnam 
 
 Trial Registration: NCT04830800 for phase 1 and NCT05940194 for phase 2 
MOH Study Number (To-be-assigned by MOH) 
 
CONFIDENTIAL 
 
Version: 2.0  
Dated: Aug 03, 2021 
 
 
 
 
Sponsored by: 
Institute of Vaccines and Medical Biologicals (IVAC)  
Nha Trang, Viet Nam 
 
 
Principal Investigator: 
Prof. Dang Duc Anh and Associate Prof. Vu Dinh Thiem 
Ha Noi, Vietnam 
 
 
 
  
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone or used 
except as authorized by IVAC 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ........................................................................................................................ 2 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................................... 7 
STATEMENT OF COMPLIANCE ...................................................................................................... 10 
PROTOCOL SIGNATURE PAGE for phase 1.................................................................................... 11 
PROTOCOL SIGNATURE PAGE for phase 2.................................................................................... 12 
KEY ROLES AND CONTACT INFORMATION .............................................................................. 13 
1. 
PROTOCOL SUMMARY ............................................................................................................ 14 
2. 
BACKGROUND AND RATIONALE ......................................................................................... 21 
2.1. 
Burden of Disease .................................................................................................................. 21 
2.2. 
Pathogen and Clinical Disease ............................................................................................... 21 
2.3. 
Transmission and Infectivity .................................................................................................. 22 
2.4. 
Vaccine Development ............................................................................................................ 22 
2.5. 
Risk of Immune Enhancement ............................................................................................... 23 
2.6. 
Introduction to COVIVAC Vaccine ....................................................................................... 24 
2.7. 
Summary of Nonclinical Studies............................................................................................ 25 
2.8. 
Study Design Rationale .......................................................................................................... 30 
2.8.1. 
Justification for Dose ...................................................................................................... 31 
2.9. 
Overall Clinical Development Strategy ................................................................................. 32 
3. 
HYPOTHESES, OBJECTIVES AND ENDPOINTS................................................................... 32 
3.1. 
Study Hypotheses ................................................................................................................... 32 
3.2. 
Study Objectives .................................................................................................................... 33 
3.2.1. 
Primary Objectives: ........................................................................................................ 33 
2     Immunogenicity: .................................................................................................................... 33 
3.2.2. 
Secondary Objectives...................................................................................................... 33 
3.2.3. 
Exploratory Objectives: .................................................................................................. 34 
3.3. 
Study Endpoints ..................................................................................................................... 34 
3.3.1. 
Primary Endpoints: ......................................................................................................... 34 
3.3.2. 
Secondary Endpoints: ..................................................................................................... 34 
3.3.3. 
Exploratory Endpoints: ................................................................................................... 35 
4. 
STUDY DESIGN.......................................................................................................................... 35 

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5. 
STUDY POPULATION ............................................................................................................... 38 
5.1. 
Study Population .................................................................................................................... 38 
5.2. 
Clinical Trial Site ................................................................................................................... 38 
5.3. 
Inclusion Criteria .................................................................................................................... 40 
5.4. 
Exclusion Criteria ................................................................................................................... 40 
5.5. 
Screen Failures ....................................................................................................................... 42 
6. 
STUDY PRODUCT...................................................................................................................... 42 
6.1. 
Product Descriptions .............................................................................................................. 42 
6.2. 
Stability and Storage .............................................................................................................. 42 
6.3. 
Preparation and Administration ............................................................................................. 43 
6.4. 
Accountability and Disposal .................................................................................................. 44 
7. 
STUDY PROCEDURES .............................................................................................................. 44 
7.1. 
Recruitment ............................................................................................................................ 44 
7.1.1. 
Initial and Continuing Informed Consent ....................................................................... 45 
7.2. 
Study Visits ............................................................................................................................ 45 
7.2.1. 
Screening (Day -42 to Day 1) ......................................................................................... 47 
7.2.2. 
Visit 1 (Day 1) ................................................................................................................ 47 
7.2.3. 
Visit 2 (Day 8) and Visit 4 (Day 36)............................................................................... 49 
7.2.4. 
Visit 3 (Day 29) .............................................................................................................. 50 
7.2.5. 
Visit 5 (Day 43) .............................................................................................................. 51 
7.2.6. 
Visit 6 (Day 57) .............................................................................................................. 52 
7.2.7. 
Visit 7 (Day 197) ............................................................................................................ 52 
7.2.8. 
Visit 8 (Day 365, EOS) (phase 1 only) ........................................................................... 53 
7.2.9. 
Unscheduled Contacts and Visits ................................................................................... 53 
7.3. 
Subject Discontinuation ......................................................................................................... 53 
7.4. 
Concomitant Medications ...................................................................................................... 54 
7.5. 
Emergency Unblinding Procedure ......................................................................................... 55 
7.6. 
Management of Pregnancy ..................................................................................................... 55 
7.7. 
Clinical Procedures ................................................................................................................ 55 
8. 
SAFETY ASSESSMENT AND REPORTING ............................................................................ 56 
8.1. 
Collection of Safety Events .................................................................................................... 56 
8.2. 
Definitions .............................................................................................................................. 56 

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8.2.1. 
Adverse Event ................................................................................................................. 56 
8.2.2. 
Solicited Adverse Event .................................................................................................. 57 
8.2.3. 
Unsolicited Adverse Event ............................................................................................. 57 
8.2.4. 
Medically-Attended Adverse Event ................................................................................ 57 
8.2.5. 
Adverse Event of Special Interest ................................................................................... 57 
8.2.6. 
Protocol-Related Adverse Event ..................................................................................... 58 
8.2.7. 
Treatment-Emergent Adverse Event ............................................................................... 58 
8.2.8. 
Serious Adverse Event .................................................................................................... 58 
8.2.9. 
Severity (Intensity) of Adverse Event............................................................................. 59 
8.2.10. 
Causal Relationship of an Adverse Event ................................................................... 59 
8.2.11. 
Assessment of Outcome of Adverse Event ................................................................. 60 
8.3. 
Adverse Event Recording and Reporting ............................................................................... 60 
8.4. 
Serious Adverse Event Reporting .......................................................................................... 60 
8.5. 
Unanticipated Problems ......................................................................................................... 61 
9. 
SAFETY MONITORING ............................................................................................................. 61 
9.1. 
Protocol Safety Review Team ................................................................................................ 61 
9.2. 
Data and Safety Monitoring Board ........................................................................................ 61 
9.3. 
Pause Rules ............................................................................................................................ 62 
9.4. 
Protocol Deviation .................................................................................................................. 62 
10. 
STATISTICAL CONSIDERATIONS....................................................................................... 63 
10.1. 
Overview and General Considerations ............................................................................... 63 
10.2. 
Randomization Procedures ................................................................................................. 63 
10.3. 
Sample Size and Power ...................................................................................................... 64 
10.4. 
Definitions of Populations to be Analyzed ......................................................................... 66 
10.4.1. 
Enrolled Population ..................................................................................................... 66 
10.4.2. 
Exposed Population ..................................................................................................... 66 
10.4.3. 
Safety Analysis Population ......................................................................................... 66 
10.4.4. 
Full Analysis Population ............................................................................................. 66 
10.4.5. 
Per Protocol Population ............................................................................................... 66 
10.5. 
Analysis Sequence and Analytical Methodology ............................................................... 66 
10.5.1. 
Analysis of Demographic and Baseline Characteristics ............................................. 67 
10.5.2. 
Analysis of Primary Safety Objectives ....................................................................... 67 

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10.5.3. 
Analysis of Immunogenicity objectives (Secondary Objectives for the Phase 1, 
Primary Objective for the Phase 2) ............................................................................................... 68 
10.5.4. 
Analysis of Exploratory Objectives ............................................................................ 69 
10.6. 
Multiplicity ......................................................................................................................... 69 
10.7. 
Handling of Subject Discontinuations and Missing Data ................................................... 70 
11. 
LABORATORY EVALUATIONS ........................................................................................... 70 
11.1. 
Blood Sample Collection, Distribution, and Storage ......................................................... 70 
11.2. 
Safety Clinical Laboratory Assays ..................................................................................... 71 
11.3. 
Immunological Assays (Secondary Objectives) ................................................................. 71 
11.4. 
Microbiological Assays ...................................................................................................... 71 
11.5. 
Assay Qualification, Standardization, and Validation........................................................ 71 
11.6. 
Biohazard Containment ...................................................................................................... 72 
12. 
DATA MANAGEMENT ........................................................................................................... 72 
12.1. 
Case Report Form Development and Completion .............................................................. 72 
12.2. 
Record Archival .................................................................................................................. 73 
12.2.1. 
Archiving Data at Study Site ....................................................................................... 73 
12.2.2. 
Data Storage and Archival .......................................................................................... 73 
12.3. 
Posting of Information on Clinicaltrials.gov ...................................................................... 73 
12.4. 
Confidentiality .................................................................................................................... 73 
12.5. 
Publication .......................................................................................................................... 74 
13. 
QUALITY ASSURANCE AND QUALITY CONTROL ......................................................... 74 
13.1. 
General Considerations ....................................................................................................... 74 
13.2. 
External Monitoring ........................................................................................................... 74 
13.3. 
Independent Auditing ......................................................................................................... 75 
13.4. 
Regulatory Agency Auditing .............................................................................................. 75 
14. 
OBLIGATIONS AND ROLES OF THE SPONSOR, PI, AND STUDY PERSONNEL ......... 75 
15. 
ETHICAL CONSIDERATIONS AND INFORMED CONSENT ............................................ 76 
15.1. 
Ethical Review .................................................................................................................... 76 
15.2. 
Informed Consent Process .................................................................................................. 76 
15.3. 
Study-Related Injury........................................................................................................... 77 
15.4. 
Risk/Benefit ........................................................................................................................ 77 
15.5. 
Subject Confidentiality ....................................................................................................... 78 
15.6. 
Reimbursement ................................................................................................................... 78 

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15.7. 
Storage of Specimens ......................................................................................................... 78 
16. 
APPENDICES ........................................................................................................................... 80 
16.1. 
Appendix 1:  Solicited Injection Site and Systemic Reactions Toxicity Grading Table.... 80 
16.2. 
Appendix 2:  Vital Signs Toxicity Grading Table .............................................................. 82 
16.3. 
Appendix 3: Serum and Hematology Toxicity Grading Table........................................... 83 
16.4. 
Appendix 4: Potential Immune-Mediated Medical Conditions (PIMMC) ......................... 84 
16.5. 
Appendix 5: Adverse Events Specific to COVID-19 Disease ........................................... 86 
16.6. 
Appendix 6: Template of interim study report for transition to Phase 2 ............................ 87 
16.7. 
Appendix 7: References ...................................................................................................... 88 
 
List of tables and figures in the protocol: 
- 
Table 1. Summary of preclinical studies 
- 
Table 2. COVIVAC Treatment Groups (Toxicology Study) 
- 
Table 3.  Treatment Groups 
- 
Table 4.  Phase 1 Dose Escalation Steps 
- 
Table 5.  Schedule of Study Visits and Procedures – Phase 1 and Phase 2 
- 
Table 6. 
Severity Grading 
- 
Table 7. Probability to observe at least one serious or severe adverse event by sample size and 
underlying event rate. 
- 
Table 8. Power to select the candidate with the highest true mean to progress to second phase and 
overall for the Phase 1/2 overall by minimum fold-difference between the highest candidate mean 
and the other means, assuming log10 variability of 0.5. 
- 
Table 9.   Blood Volume Requirements 
 
 

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LIST OF ABBREVIATIONS AND ACRONYMS 
ABBREVIATION/ 
ACRONYM 
DEFINITION 
Ab 
antibody 
ACE2 
angiotensin-converting enzyme 2 
ADCC 
antibody-dependent cellular cytotoxicity 
ADE 
antibody-dependent enhancement 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase 
ANCA 
anti-neutrophil cytoplasmic antibody 
ARDS 
acute respiratory distress syndrome 
AST 
aspartate transaminase 
ATC 
anatomical therapeutic chemical 
BMI 
Body Mass Index 
BPL 
beta-propiolactone 
C 
Celsius 
CAPA 
corrective action and preventive action 
CBER 
Center for Biologics Evaluation and Research 
CDC 
Centers for Disease Control and Prevention 
CI 
confidence interval 
Cm 
CMI 
Centimeter 
cell-mediated immunity 
COVID-19 
coronavirus disease 2019 (disease caused by SARS-CoV-2) 
CREST 
calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, 
and telangiectasia 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
D 
day(s) 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
EDC 
electronic data capture 
ELISA 
ELISpot 
enzyme-linked immunosorbent assay 
enzyme-linked immunospot 
ELU 
ELISA Units 
EOS 
end of study 
ER 
Emergency Room 
EUA 
Emergency Use Authorization 
F 
Fahrenheit 
FDA 
US Food and Drug Administration 
FIPV 
feline infectious peritonitis virus  
G 
Group 
GCP 
good clinical practice 
GLP 
good laboratory practice 
GMC 
geometric mean concentration 
GMFR 
geometric mean fold rise 
GMP 
good manufacturing practice 
GMT 
geometric mean titer 

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HBsAg 
hepatitis B surface antigen 
hCG 
serum human gonadotrophic hormone 
HCV Ab 
hepatitis C virus antibody 
Hgb 
hemoglobin 
HIV 1/2 Ab 
human immunodeficiency virus 1 and 2 antibody 
HMU 
Hanoi Medical University 
HN 
hemagglutinin-neuraminidase 
HXP 
HexaPro 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ID 
identification 
IIV 
inactivated influenza virus vaccine 
IgG 
immunoglobulin G 
IL 
interleukin 
IM 
intramuscular 
IME 
important medical event 
IN 
intranasal 
INF 
interferon 
ISO 
International Organization for Standardization 
IP 
investigational product 
 
ISMMS 
Icahn School of Medicine at Mount Sinai 
IV 
intravenous 
IVAC 
Institute of Vaccines and Medical Biologicals 
IWRS 
Interactive Web Response System 
LMIC 
low- and middle-income country 
LSLV 
last subject last visit 
MAAE 
medically-attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS-CoV 
Middle East respiratory syndrome coronavirus 
MIS-C 
multisystem inflammatory syndrome in children 
mm 
millimeter 
MoH 
Ministry of Health 
N 
nucleocapsid  
NAb 
neutralizing antibody 
NDV 
Newcastle disease virus 
NICVB 
National Institute for Control of Vaccines and Biological 
NIHE 
National Institute of Hygiene and Epidemiology 
NT50 
50% neutralizing antibody titer 
NT80 
80% neutralizing antibody titer 
NTF 
PBMC 
note to file 
peripheral blood mononuclear cell 
PBS 
phosphate-buffered saline 
PE 
physical examination 
PI 
principal investigator (the term is used throughout to indicate PI or 
designee) 
PIMMC 
potential immune-mediated medical conditions 
Plt 
platelet 
PNA 
pseudovirus neutralization assay 
PPE 
personal protective equipment 

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PP IMM 
per protocol immunogenicity population 
PSRT 
Protocol Safety Review Team 
qPCR 
quantitative polymerase chain reaction 
R 
recovery 
R0 
reproduction number 
RLU 
relative luminescence units 
RNA 
ribonucleic acid 
RSV 
respiratory syncytial virus 
RT-PCR 
reverse transcription polymerase chain reaction 
S 
Spike 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV 
severe acute respiratory syndrome coronavirus 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
SOC 
system organ class 
SOP 
standard operating procedure 
SSP 
study-specific procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TEN 
toxic epidermal necrolysis 
Th 
T-helper cell 
TLR-9 
toll-like receptor 9 
TMF 
trial master file 
US 
United States 
USP 
V 
United States Pharmacopeia 
Visit number (e.g. V1 = first study visit) 
WBC 
white blood cell 
WHO 
World Health Organization 
WMA 
World Medical Association 
WOCBP 
Women of childbearing potential 
WT 
wild-type 
 
 
 

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STATEMENT OF COMPLIANCE 
I am Principal Investigator of the study “A Phase 1/2 Randomized, Placebo-controlled (phase 1) and 
Active-controlled (phase 2), Observer-blind Trial to Assess the Safety and Immunogenicity of 
COVIVAC Vaccine produced by IVAC in Adults ≥ 18 and ≥ 60 years old in Vietnam”; signing 
below ensures that the study will be carried out on schedule, according to the content of approved 
protocol, and in accordance with Good Clinical Practice (GCP) as required by applicable rules of 
Vietnam: Decision No. 799/2008/QD-BYT dated 07 Mar, 2008, on “Guidance on Good Clinical 
Practice,” Circular No. 29/2018/TT-BYT dated 29 Oct, 2018 on “Regulation on Clinical Trial” and 
the Circular No. 32/2018/TT/BYT dated 12 Nov, 2018 on “Regulation on Medical Product 
Registration and Input Materials,” Decision 1248/QD BYT dated 11 Jan, 2013, on the National 
Guidelines on ethical issues in biomedical research; Circular 04/2020/TT-BYT dated 05 Mar, 2020 
on the Establishment, Functions and Responsibilities of Biomedical Ethics Committee, and Dispatch 
No 62/QĐ-K2ĐT dated 02 Jun, 2017, on the guidelines on recording/reporting SAEs in a clinical 
trial. And the Decision No 3659/QĐ-BYT dated 21 Aug, 2020 on “Guidance on Research, Clinical 
Trial, Licensing and Use of COVID-19 vaccine”. 
The study informed consent documents will embody the elements of consent as described in the 
Declaration of Helsinki. 
The study will also be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
• 
International Conference on Harmonisation (ICH) Guidance for GCP E6(R2) 
• 
World Medical Association (WMA) Declaration of Helsinki – Ethical Principles for Research 
Involving Human Subjects (Oct 2013 or subsequent amendments) 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training and ICH-GCP training prior to interaction with any 
participants or to have access to their confidential study data. 
 
 
 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
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PROTOCOL SIGNATURE PAGE FOR PHASE 1 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and ICH-GCP guidelines as outlined in the ‘Statement of Compliance.’ 
 
Site Investigator: 
Signed: 
Date: 
 
Name: Associate Prof. Vu Dinh Thiem, MD 
Title: Director of Clinical Trial Center, NIHE 
 
 
Signed: 
Date: 
 
Name: Prof. Dang Duc Anh, MD 
Title: Director of NIHE 
 
 
Co-Investigator: 
Signed: 
Date: 
 
Name: Ta Thanh Van 
Title: Committee Chair of HMU 
 
Signed: 
Date: 
 
Name: Pham Thi Van Anh 
Title: CRU head of HMU 

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PROTOCOL SIGNATURE PAGE FOR PHASE 2 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and ICH-GCP guidelines as outlined in the ‘Statement of Compliance.’ 
 
Site Investigator: 
Signed: 
Date: 
 
Name: Associate Prof. Vu Dinh Thiem, MD 
Title: Director of Clinical Trial Center, NIHE 
 
 
Signed: 
Date: 
 
Name: Prof. Dang Duc Anh, MD 
Title: Director of NIHE 
 
 

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KEY ROLES AND CONTACT INFORMATION 
Sponsor 
Institute of Vaccines and Medical Biologicals (IVAC) 
Clinical Trial Center 
National Institute of Hygiene and Epidemiology (NIHE) 
Principal Investigator 
Prof. Dang Duc Anh 
Co- Principal Investigator 
Associate Prof. Vu Dinh Thiem, MD 
Vaccine Manufacturer 
IVAC 
Contract Research Organization for 
clinical monitoring 
Vietstar 
Contract Research Organization for 
data management 
Local CRO with experience and collaboration with 
international CRO on data management will be contracted in 
order to meet the requirements in the ICH E6-R2 and 
electronic data security. 
Clinical site 
Hanoi Medical University (HMU) for Phase 1. 
Vu Thu Districthealth center and commune health centers, 
Thai Binh province for Phase 2 
Immunology Laboratory 
Nexelis 
525 Cartier West Blvd  
Laval, Quebec 
Canada, H7V 3S8 
Clinical Laboratory 
Clinical lab of HMU’s Hospital.   
No 1, Ton That Tung Street, Hanoi, Vietnam (for phase 1) 
 
Microbiology Laboratory 
Laboratory of virus transmitted from animal to human, Virus 
Lab Department of NIHE 
Ethics Committees 
NIHE’s IRB and Independent Ethics Committee of MoH 
 
National Regulatory Agency 
Ministry of Health (MoH) in Vietnam 
Sponsor Medical Monitor: 
Associate Prof. Le Van Be 
Technical support 
PATH Vietnam office 
11th Floor, Hanoi Towers 
49 Hai Ba Trung 
Hoan Kiem District 
Hanoi, Vietnam  
 
PATH US office 
2201 Westlake Avenue, Suite 200.  
Seattle, WA 98121, USA 
 
 
 

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1. PROTOCOL SUMMARY 
TITLE 
A Phase 1/2 Randomized, Placebo-controlled (phase 1) and Active-controlled 
(phase 2), Observer-blind Trial to Assess the Safety and Immunogenicity of 
COVIVAC Vaccine produced by IVAC in Adults ≥ 18 and ≥ 60 years old in 
Vietnam 
STUDY NUMBER 
 
PROJECT PHASE 
Phase ½ 
INVESTIGATIONAL 
PRODUCT(S) 
Investigational Vaccine: 
Inactivated Newcastle Disease Virus (NDV) chimera expressing a trimeric pre-
fusion form of the SARS-CoV-2 Spike (S) protein that contains six proline 
mutations (HexaPro, HXP); for intramuscular (IM) administration. One 
formulation of COVIVAC evaluated in this study (phase 1) includes 1.5 mg of the 
adjuvant CpG 1018 (a 22-mer phosphorothioate-linked oligodeoxynucleotide).  
Control product of Phase 1: 
Placebo: (Phosphate-buffered saline (PBS); for IM administration) 
Control product of Phase 2: 
Authorized Covid-19 vaccine: AstraZeneca AZD1222 
STUDY HYPOTHESES Safety, Tolerability: 
• 
COVIVAC will have an acceptable safety profile and be well-tolerated at all 
dose levels when administered as a two-dose regimen either without adjuvant 
(at 1 µg, 3 µg, and 10 µg of S protein per 0.5 ml dose), or with the adjuvant 
CpG 1018 (at 1 µg of S protein per 0.5 ml dose) in the phase 1 part of the study, 
and at an addition dose of 6 ug dose in the phase 2 of the study). Safety and 
tolerability of the vaccine will be comparable to those of AstraZeneca vaccine, 
which will be used as an active comparator in the phase 2 study. 
Immunogenicity: 
• 
COVIVAC will elicit a measurable and dose-dependent neutralizing antibody 
response, comparable to that of the AstraZeneca vaccine 
STUDY OBJECTIVES 
– PHASE 1 
Primary Objective: 
Safety, Tolerability: 
1. To assess the safety and tolerability of each of four formulations of COVIVAC 
(at 1, 3 and 10 µg without adjuvant; and at 1 µg with CpG 1018) after the first 
and second dose of a two-dose regimen administered at a 28-day interval to 
adults aged 18-59 years  
Secondary Objectives: 
Immunogenicity: 
1. To assess the functional (neutralizing) humoral immune response elicited by 
each formulation of NDV-HXP-S, as measured by a SARS CoV-2 pseudovirus-
based neutralization assay (PNA), at baseline, 28 days after the first 
vaccination, and 14 days after the second vaccination (to inform the selection of 
two formulations for evaluation in Phase 2), and at 6 months after the second 
vaccination, in adults aged 18-59 years  

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2. To assess the Immunoglobulin G (IgG) immune response elicited by each 
formulation of COVIVAC against the S protein of SARS-CoV-2, as measured 
by enzyme-linked immunosorbent assay (ELISA), at baseline, 28 days after the 
first vaccination, and 14 days and 6 months after the second vaccination, in 
adults aged 18-59 years 
STUDY OBJECTIVES 
– PHASE 2 
Primary Objective: 
1) Safety, Tolerability: 
1. To assess the safety and tolerability of two dose levels of COVIVAC, 3 µg 
(evaluated in Phase 1) and 6 µg, (an intermediate dose level to select based on 
the Phase 1 safety and immunogenicity data). Safety and tolerability will be 
assessed after the first and second dose of a two-dose regimen administered at a 
28-day interval to adults 18to  >60 years old, for each dose level and in 
comparison with those of the AstraZeneca vaccine, the active comparator. 
2. To assess the safety and tolerability of the two selected doses of COVIVAC (3 
µg and 6 µg)  separately for individual  aged 18-59 years and ≥60 years 
2) 2- Immunogenicity: 
1. To assess the functional (neutralizing) humoral immune response elicited by 
each of two selected COVIVAC formulations, as measured by PNA, at 
baseline, and 14 days and 6 months after the second vaccination, in adults 18- 
>60 years old 
2. To assess the functional (neutralizing) humoral immune response elicited by 
each of two selected COVIVAC formulations, as measured by PNA, at 
baseline, and 14 days and 6 months after the second vaccination, separately in 
adults aged 18-59 years and ≥60 years 
3. To assess the IgG immune response elicited by each of two selected COVIVAC 
formulations against the S protein of SARS-CoV-2, as measured by ELISA, at 
baseline and 14 days and 6 months after the second vaccination, in adults 18 
>60 years old 
4. To assess the IgG immune response elicited by each of two selected COVIVAC 
formulations against the S protein of SARS-CoV-2, as measured by ELISA, at 
baseline and 14 days and 6 months after the second vaccination, separately in 
adults aged 18-59 years and ≥60 years 
5. To compare the immune responses observed at each dose level of COVIVAC 
with the corresponding responses observed with the AstraZeneca active 
comparator vaccine. 
Exploratory Objectives (Immunogenicity): 
1. To assess the S protein-specific T cell response elicited by each of two selected 
COVIVAC formulations, as measured by enzyme-linked immunospot assay 
(ELISpot), at baseline, and 14 days and 6 months after the second vaccination, 
in a subset of adults 18 - >60 years old 
2. To assess the S protein-specific T cell response elicited by each of two selected 
COVIVAC formulations, as measured by ELISpot, at baseline, and 14 days and 
6 months after the second vaccination, separately in a subset of adults aged 18-
59 years and ≥60 years 

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STUDY ENDPOINTS 
Primary Endpoints: 
1- Safety, Tolerability: 
• 
Number and severity of solicited local and systemic adverse events (AEs) 
during the first 7 days after each vaccination  
• 
Number, severity, and relatedness of clinically significant hematological and 
biochemical measurements at 7 days post each vaccination (for Phase 1 only) 
• 
Number, severity and relatedness of all unsolicited AEs during the first 28 days 
after each vaccination  
• 
Number, severity and relatedness of serious adverse events (SAEs) throughout 
the entire study period 
• 
Number, severity and relatedness of medically-attended AEs (MAAEs) 
throughout the entire study period 
• 
Number, severity and relatedness of adverse events of special interest (AESI) 
throughout the entire study period, including AESI relevant to COVID-19, and 
potential immune-mediated medical conditions (PIMMC)  
: 
Immunogenicity Endpoints: 
For Primary and Secondary Objectives: 
• 
50% neutralizing antibody (NT50) and 80% neutralizing antibody (NT80 - Phase 
1 only) geometric mean titer (GMT) against SARS-CoV-2 pseudovirus at 
baseline, 28 days after the first vaccination (for Phase 1 subjects only), and 14 
days and 6 months after the second vaccination in subjects who are anti-S IgG 
seronegative at baseline 
• 
Geometric mean fold rise (GMFR) (from baseline) in NT50 and NT80 (Phase 1 
only) against SARS-CoV-2 pseudovirus at 28 days after the first vaccination 
(for phase 1 subjects only), and 14 days and 6 months after the second 
vaccination 
• 
Percentage of subjects with NT50 and NT80 (Phase 1 only) seroresponses against 
SARS-CoV-2 pseudovirus as defined by (1) a ≥ 4-fold increase from baseline, 
and (2) a ≥ 10-fold increase from baseline at 28 days after the first vaccination 
(for Phase 1 subjects only), and 14 days and 6 months after the second 
vaccination 
For Secondary Objective 2 (Phase 1), and Primary Objectives 1-45 (Phase 2):  
• 
Anti-S IgG GMT at 28 days after the first vaccination (for Phase 1 subjects 
only), and 14 days and, 6 months after the second vaccination in subjects who 
are anti-S IgG seronegative at baseline 
• 
GMFR (from baseline) in anti-S IgG GMT at 28 days after the first vaccination 
(for Phase 1 subjects only), and 14 days, 6 months after the second vaccination 
• 
Percentage of subjects with seroresponses in anti-S IgG titer as defined by (1) a 
≥ 4-fold increase from baseline, and (2) a ≥ 10-fold increase from baseline, at 
28 days after the first vaccination (for Phase 2 subjects only), and 14 days and 6 
months after the second vaccination 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
17 
For Exploratory Objectives 1 and 2 (Phase 2): 
• 
Magnitude, functionality, and T-helper cell (Th) polarization of S protein-
specific T cells relative to baseline at 14 days and 6 months after the second 
vaccination 
• 
 
STUDY DESIGN 
This prospective, single-center, randomized, placebo-controlled (phase 1) and 
active-controlled (phase 2), observer-blind Phase 1/2 study includes two separate 
parts.  
Part 1 is a first-in-human, Phase 1 study designed to evaluate the safety, tolerability 
and immunogenicity of the COVIVAC vaccine at three different dose levels (1, 3, 
and 10 µg) without adjuvant, and at one dose level (1 µg) with the adjuvant CpG 
1018, in a total of 120 subjects aged 18-59 years. Eligible subjects will be randomly 
assigned to receive study vaccine or placebo as an IM injection in the deltoid 
muscle at Visit [V]1 as part of one of four sequential groups of escalating antigen 
dose level or added adjuvant. Each group will be divided into two sequential 
subgroups, a sentinel subgroup (n=6) and a larger subgroup (n=24) that includes the 
remaining subjects to be evaluated at that dose level (or for that formulation in the 
case of the one adjuvanted treatment group). Initially, a sentinel subgroup of 6 
subjects will be randomized to receive COVIVAC 1 µg or placebo in a 5:1 ratio. 
Sentinel subjects will be monitored for reactogenicity and safety through Day 8 
(Visit 2), including for the initial 24 hours post-injection in clinic. If the Protocol 
Safety Review Team (PSRT) has no safety concerns based on blinded review of all 
safety data, including clinical laboratory results, through Visit 2, the second 
subgroup of 24 subjects will be randomized to receive COVIVAC 1 µg or placebo 
at the same ratio; on the same day, the sentinel subgroup  (n=6) for the second dose 
level to be evaluated (COVIVAC 3 µg) can be randomized to receive study vaccine 
or placebo in a 5:1 ratio, and so on for the subsequent dose level and formulation 
(see Table 4).   
The PSRT will review blinded safety, reactogenicity and clinical laboratory data 
accrued on a weekly basis until D43 of the last subject in each phase, then at least 
once monthly until the end of the study. Subjects will receive 2 doses of assigned 
investigational product (IP) on D1 and D29 (V1 and V3), and be assessed in clinic 
for safety and reactogenicity at 7 days after each vaccination (V2 and V4, [ phase 1 
only) for safety at 28 days after the second vaccination (V6), and for safety and 
immunogenicity assessments at baseline (V1), 28 days after the first vaccination 
(V3) and 14 and 168 days after the second vaccination (V5 and V7, end-of-study 
[EOS] Visit) (see Visit Schedule Table below).  
An interim analysis of Phase 1 data conducted after the last subject last visit for V6 
(D57) will serve as the basis for decisions about down-selection and advancing to 
Part 2 of the study (Phase 2). Down selection and advancement to Part 2 (Phase 2) 
will be based on the following parameters: 
• 
Post-dose 2 immunogenicity results at the aggregate treatment level  
o A threshold immune response at Day 43 will be required: the observed 
seroresponse rate in a treatment group (defined as the percentage of 
subjects with at least a 4-fold rise from baseline in  neutralizing antibody 
titers) will need to be ≥52% at the LL of the 95% CI for that treatment 
(vaccine formulation) to be considered for advancement to Phase 2. 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
18 
• 
Post-dose 1 and post dose 2 safety results including all solicited and unsolicited 
adverse events, serious adverse events, and clinical laboratory results. 
  
The following process will be followed for the decision about down selection and 
advancing to Part 2 (Phase 2):  
• 
The DSMB will review the unblinded safety data and provide a 
recommendation to the Sponsor on whether the safety profile is acceptable for 
advancing a formulation to Phase 2.  
• 
The Sponsor will review the DSMB recommendation in conjunction with the 
immunogenicity data, and the post-dose 1 and dose 2 safety results at the 
aggregate treatment level (in the case of rare events occurring in only one 
treatment group, these will be added with an asterisk in all groups for Sponsor 
review); to select two formulations to advance to Phase 2. 
o If multiple formulations achieve the threshold immune response (as well as 
have an adequate safety and tolerability profile per the DSMB), the 
Sponsor will select two formulations to advance to Phase 2 based on 
consideration of such factors as the relative functional immunogenicity of 
these formulations, opportunity for dose sparing, and opportunity to limit 
cost and possible supply constraints associated with use of the CpG 
adjuvant.   
o If the data from the phase 1 suggests that an intermedium dose of vaccine 
is more appropriate (given the practicality of using 10 ug of vaccine as the 
final dose) that dose will be selected for the Phase 2 study. 
• 
The selection and recommendation to advance to Phase 2 along with the interim 
report will be jointly reviewed by NIHE’s IRB and MoH prior to Phase 2 
enrollment.  
In Part 2 of this combined Phase 1/2 study, 375 adults aged 18 to ≥ 60 years of aged 
will be randomized  (1:1:1)  to comparator vaccine, or one of two selected doses of 
COVIVAC, 3µg (being evaluated in Phase 1) and 6µg (an intermediate dose level 
not tested in the Phase 1, but lower than the maximum tested on the Phase 1 trial). 
We aim to enroll at least cone-third of the Phase 2 subjects  in the age range ≥60 
years to ensure that adequate safety and immune data will be available from older 
and elderly adults to inform the selection of the COVIVAC formulation to advance 
to Phase 3 studies. The Phase 2 cohort will follow the same visit schedule, and 
undergo the same procedures and assessments, as in Phase 1 (except  that the 
V4/D36 visit is conducted by phone/home visit instead of site visit and no blood 
will be collected for immunogenicity testing on Day 28 (i.e., 4 weeks after the first 
dose). In addition, as exploratory objectives, the anti-NDV HN IgG response will be 
assessed at V1, V3, V5, and V7 in all subjects in phase 1 if a laboratory is 
determined as capable of doing this test, and 36 subjects (equally distributed 
between the three age strata) will be randomly selected in a 1:1:1 ratio to provide 
additional blood at V1, V5 and V7 to be used to isolate peripheral blood 
mononuclear cells (PBMCs) for assessment of T-cell-mediated immunity (CMI). 
An interim analysis of Phase 2 data  will be conducted after the last subject of the 
Phase 2 cohort completes V6 (D57) as the basis for selecting the optimal 
formulation of COVIVAC to advance to Phase 3 studies. As was the case for the 
Phase 1 interim analysis at the same timepoint, the data generated will include 
unblinded post-dose 1 and dose 2 safety results for review by the DSMB which 
includes safety results at the aggregate treatment level (in the case of rare events 
occurring in only one treatment group, these will be added with an asterisk in all 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
19 
groups for Sponsor review)   and immunogenicity results aggregated by treatment 
group.. The DSMB will consider all accumulated safety data from both phases of 
the study prior to making any recommendation to the Sponsor that it not advance a 
formulation based on safety concerns. The Sponsor will ultimately select the 
formulation to advance to Phase 3 based on the DSMB assessment of safety and 
tolerability profile, the  relative functional immunogenicity and other programmatic 
considerations such as those noted above. 
TREATMENT GROUPS 
Phase 
Group 
Sample Size 
Study Product 
1 
1 
20 
Placebo 
2 
25 
COVIVAC 1 µg 
3 
25 
COVIVAC 3 µg  
4 
25 
COVIVAC 10 µg 
5 
25 
COVIVAC 1 µg + CpG 1018 1.5 mg 
2 
1 
125 
AstraZeneca 
2 
125 
COVIVAC 3 µg 
3 
125 
COVIVAC 6 µg  
 
VISIT SCHEDULE – PHASE 1 AND PHASE 2 
  
V1 
V2 
V3 
V4$ 
V5 
V6 
V7 
 
Day 
(+ window) 
-42 to 1 
1 
8 
(+3) 
29 
(+3) 
36 
(+3) 
43 
(+3) 
57 
(+7) 
197 (+14) 
 
Screening 
X 
  
  
 
  
  
 
   
Vaccination 
  
1 
  
2 
  
  
 
   
Immune labs  
   Pseudovirus 
   ELISAs*    
  
X 
  
X 
  
X$ 
 
X  
   CMI
# 
 
X 
 
X 
 
X 
 
X 
             Safety data collection: 
Safety visits 
X 
X 
X 
X 
X$ 
X 
X 
X 
Clinical labs@ 
X@ 
  
X$ 
 
X$ 
  
 
  
  
Reactogenicity 
  
  
 
  
 
  
  
AEs 
  
  
  
MAAEs 
  
AESI 
  
SAEs 
  
* Anti-NDV ELISA in Phase 2 only, at V1, V3, V5, and V7 
# Phase 2 only, in subset of subjects 
$ Phase 1 only. In Phase 2, study staff will make a phone call/home visit to remind subject to complete the diary card; 
the diary card for dose 2 will be collected and reviewed on the V5/D43 visit (2 weeks after vaccination) 
@ Phase 1 only. 
Note: The study dates of visits after the V3/D29 visit will be adjusted according to the actual date of the V3/D29 visit. 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
20 
STUDY POPULATION 
A total of 495 male and female adults ≥ 18 years old will receive Investigational 
Product (IP) and be evaluated for safety and immunogenicity as part of this 
combined Phase 1/2 study. At least one-third of the subjects evaluated in Phase 2 
will be ≥60 years old. Phase 1 of the study will be conducted at Hanoi Medical 
University (HMU) and Phase 2 of the study will be conducted at Vu Thu district 
health center and commune health centers of Vu Thu district, Thai Binh province. 
STUDY DURATION 
Subjects will be followed for approximately 7 months after randomization (6 
months following dose 2 of IP). 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
21 
2. BACKGROUND AND RATIONALE 
On 7 January 2020, a novel coronavirus was identified as the cause of a cluster of pneumonia cases 
first detected in December 2019 in Wuhan, the capital of China’s Hubei province,1 marking the third 
documented zoonotic transmission event of a coronavirus within the last two decades. Two other 
highly pathogenic coronaviruses,1 both of the genus Betacoronavirus, also crossed the species barrier 
during this period: severe acute respiratory syndrome virus (SARS-CoV), which emerged in 
Guangdong province, China in November 2002, and ultimately led to 8,096 reported cases and 774 
deaths in 27 countries before the last infection was detected in July 2003; and the Middle East 
respiratory syndrome coronavirus (MERS-CoV), which was first detected in Saudi Arabia in June 
2012 (where it still circulates in camels) and has led to 2494 laboratory-confirmed cases and 858 
deaths.2 Phylogenic analysis from full-genome sequencing of the novel coronavirus (which became 
publicly available on 12 January 2020 [GenBank accession no. MN908947.2]  indicated that it was 
also a Betacoronavirus, and that it belonged to the same subgenus (subgenus Sarbecovirus [subgroup 
B]) as SARS-CoV, with which it shares 79% nucleotide identity.3 Given its taxonomic relationship to 
SARS-CoV, the novel coronavirus was designated severe acute respiratory syndrome virus 2 
(SARS-CoV-2) by the International Committee on Taxonomy of Viruses. By 30 January 2020, the 
international outbreak of SARS-CoV-2 was declared a Public Health Emergency of International 
Concern by the World Health Organization (WHO), which on 11 February 2020 named the disease 
caused by the virus COVID-19 (coronavirus disease 2019). By March 11, 2020, WHO officially 
declared the outbreak of COVID-19 a global pandemic. 
2.1. 
Burden of Disease 
As of 06 January, 2021, the confirmed global case count of COVID-19 has risen to over 87 million, 
and deaths directly due to SARS-CoV-2 infection have surpassed 1.85 million.4 The large majority of 
deaths have occurred among the elderly in the United States, Brazil, India and Mexico, which may be 
largely attributable to poorly implemented control measures (such as surveillance, border closure, 
quarantine and social distancing) in those countries.5 While there have been significantly fewer cases 
to date in most low- and middle-income countries (LMICs), there is great concern about the potential 
impact of easing of containment efforts, particularly in countries where robust and functioning public 
health infrastructure is lacking.6 In addition to the potentially devastating direct disease burden of 
SARS-CoV-2 in LMICs, the disruptions to routine health services and economic systems due to the 
pandemic may result in an indirect disease burden of equal or even greater magnitude – a burden that 
would be borne by all demographic groups. One study has estimated that disruptions to health 
systems and access to food in LMICs as a result of the COVID-19 pandemic would result in a 
minimum of 253,500 children under 5 child deaths and 12.200 maternal deaths over a 6-month 
period. In the worse scenario, there would be 1,157,000 additional under-five child deaths and 56.700 
maternal deaths over a 6-month period.7 In Vietnam, as of 06 January 2021 there have been 1.504 
confirmed cases and 35 deaths. 
2.2. 
Pathogen and Clinical Disease 
Like all viruses in the Coronaviridae family, SARS-CoV-2 is an enveloped, positive-sense, single-
stranded RNA virus, with a genome that (in addition to a replicase and accessory proteins) encodes 
four major structural proteins: the spike surface glycoprotein (S), small envelope protein, matrix 
protein, and nucleocapsid (N) protein. The diagnosis of COVID-19 is made by detection of 
SARS-CoV-2 RNA by reverse transcription polymerase chain reaction (RT-PCR), with a common 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
22 
gene target being one of the structural proteins. The coronavirus S protein plays the essential role of 
mediating cell entry by binding to the host-cell receptor, and thus is the primary determinant of viral 
tropism.8 The S proteins of SARS-CoV and SARS-CoV-2 bind to the same primary host receptor, the 
angiotensin-converting enzyme 2 (ACE2) receptor, whereas MERS-CoV (which belongs to a 
different coronavirus lineage) uses dipeptidyl peptidase 4.  
As is the case for both SARS-CoV and MERS-CoV, the median incubation period of SARS-CoV-2 is 
approximately four to five days after exposure.9 Similar to SARS-CoV, pneumonia is the most 
frequent serious manifestation of SARS-CoV-2 infection, with dry cough, fever, myalgia, headache, 
dyspnea and sore throat being the most common presenting clinical features.10 Diarrhea, 
nausea/vomiting, abdominal pain,11 smell and taste disorders (i.e., anosmia and dysgeusia),12 and 
rhinorrhea are also associated with COVID-19, though less commonly. While the spectrum of 
symptomatic SARS-CoV-2 infection ranges from mild to critical, most cases of COVID-19 are mild 
(approximately 80%).13 In addition, multiple studies now suggest that asymptomatic infection may be 
very common – as high as 88% by one report.14 This is in contrast to SARS-CoV, which uncommonly 
caused mild or asymptomatic disease.15 
In patients with severe to critical disease (approximately 15% and 5% of total cases, respectively),13 
dyspnea, hypoxia, cytokine release syndrome, acute respiratory distress syndrome, shock, 
thromboembolic complications, sudden cardiac death and multiorgan failure have been reported.16 
Most patients who die from COVID-19 are older persons (~80% of deaths occur in those > 65 years 
old)17 and/or persons with underlying medical comorbidities (obesity, cardiovascular disease, 
diabetes, chronic lung disease, cancer, chronic kidney disease, hypertension),18 although severe illness 
can occur in otherwise healthy persons of any age. In rare cases children can be severely affected, 
manifesting clinically as a hyperinflammatory syndrome similar to Kawasaki disease (a rare acute 
pediatric vasculitis)19 or toxic shock syndrome;20 this syndrome has been termed multisystem 
inflammatory syndrome.21 In multiple cohort studies, male gender is strongly associated with death 
from COVID-19.22,23  
2.3. 
Transmission and Infectivity 
Like SARS-CoV, there is considerable evidence that SARS-CoV-2 originated in bats, and was 
transmitted to humans after amplification in an intermediate host such as the pangolin.24 Human-to-
human transmission is thought to occur as a result of direct contact of virus with the mucous 
membranes of the infected person, primarily via infected respiratory droplets and aerosols. The risk of 
transmission from an individual with SARS-CoV-2 infection varies by the type and duration of 
exposure, factors such as the amount of virus in respiratory secretions, and the use of preventive 
measures. The interval during which an individual with COVID-19 is infectious appears to be highly 
variable, with duration of viral shedding dependent upon the severity of the illness.25 However, it is 
known that SARS-CoV-2 can be transmitted prior to, or in the absence of the development of 
symptoms, and throughout the course of illness, with highest levels of virus in the upper respiratory 
tract – and thus perhaps highest infectivity – soon after symptom onset.26 It is not known to what 
extent asymptomatic infection has contributed to the pandemic spread of the virus.27 
2.4. 
Vaccine Development 
Based on a basic reproduction number (R0) of ~2-3,28 60% to 70% of the population would need to 
develop immunity to SARS-CoV-2 for pandemic spread to be contained in the absence of significant 
control measures. Recent seroprevalence surveys indicate that population immunity remains well 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
23 
below this threshold in countries with the highest burden of COVID-19.29 These results make clear 
that herd immunity cannot be achieved through natural infection without incurring very significant 
additional costs to society in terms of mortality, morbidity, and ongoing economic and social 
disruption, and that the only acceptable route to achieving herd immunity is widespread – and ideally 
rapid – deployment of an effective vaccine.  
Studies conducted previously in support of SARS-CoV and MERS-CoV vaccine development were 
instrumental in accelerating development of SARS-CoV-2 candidates. The fact that many COVID-19 
vaccine programs have moved quickly with selection of the S protein as target antigen was due to 
prior preclinical and human immunology studies on SARS-CoV demonstrating that the S protein of 
SARS-CoV elicits neutralizing antibodies that are protective against SARS-CoV challenge (by 
blocking virus attachment and fusion, as well as possibly by triggering FcR-mediated cytolysis or 
phagocytosis), and that these antibodies persist in convalescent serum of patients who have recovered 
from SARS.30 Not long after the onset of the COVID-19 pandemic it was similarly demonstrated that 
the S protein of SARS-CoV-2 induces anti-S IgG antibodies in infected humans that neutralize the 
virus in animal models,31 and that these antibodies persist for many months in convalescent sera.32 
While it is likely that induction of CD8+ T-cells against S as well as other viral proteins 33 plays a 
complementary role in protection after natural infection, the importance of a robust anti-S IgG 
neutralizing antibody response in protection against disease after natural infection34 or experimental 
vaccination35 is now incontrovertible., 
While there is currently no licensed vaccine to prevent COVID-19, a large number of vaccine 
candidates employing a large diversity of vaccine platforms (mRNA, DNA, subunit, viral vectors, 
nanoparticle) are in development, including 11 candidates that are currently in late stage Phase 3 
development.36 Two of these vaccines, Pfizer/BioNTech’s and Moderna’s mRNA-based vaccines that 
encode the full-length S protein with two stabilizing proline mutations (S-2P) have recently been 
shown in interim analyses to have an efficacy against COVID-19 of greater than 90% after a two-
dose regimen. These results, along with supportive early-phase study results from multiple other S-
protein-based candidate vaccines that have elicited high-titer neutralizing antibodies further validate 
the selection of the S protein as target antigen.37  
2.5. 
Risk of Immune Enhancement 
In addition to facilitating target antigen selection, preclinical studies of SARS-CoV and MERS-CoV 
vaccines have also highlighted the potential risk of a SARS-CoV-2 vaccine exacerbating disease 
caused by subsequent SARS-CoV-2 infection. An inactivated SARS-CoV vaccine was shown to 
induce disease enhancement in rhesus monkeys subsequently challenged with SARS-CoV, as a result 
of non-neutralizing antibodies generated by the vaccine against the SARS-CoV S protein.38 Such 
antibody-dependent enhancement (ADE) also occurred in cats infected with the Alphacoronavirus 
feline infectious peritonitis virus (FIPV), after being vaccinated with an inactivated FIPV vaccine.39 
Vaccine-induced non-functional antibodies cause ADE by facilitating viral entry into host cells, by 
increasing binding efficiency of virus-antibody complexes to host cells via Fc receptors on those 
cells.40  
A second mechanism by which immune enhancement of disease may occur is via vaccine-induced 
inflammation.41 Apart from activating Fc-receptor mediated endocytosis, vaccine-induced antibodies 
may elicit Fc-mediated responses, such as complement activation and antibody-dependent cellular 
cytotoxicity (ADCC), that may contribute to immunopathology. This phenomenon was observed in 
ferrets and Cynomolgus monkeys challenged with SARS-CoV following vaccination with an 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
24 
inactivated whole SARS-CoV vaccine;42 the animals developed lung immunopathology characterized 
by eosinophilic recruitment, increased mucus production and airway hyperresponsiveness. The same 
immunopathology was observed in 1966 in children given formalin-inactivated respiratory syncytial 
virus (RSV) vaccine who subsequently were infected by RSV.43 Enhancement of RSV disease in that 
study led to frequent hospitalizations and, in the youngest cohort, two deaths.44 The prominence of 
eosinophils with such lung immunopathology has often been interpreted as signifying that this 
immune enhancement was the result of Th2-biased immune responses. 
To date, there has been no evidence of antibody-dependent disease enhancement or 
immunopathology in animal studies and human trials of SARS-CoV-2 candidate vaccines. This is 
likely due to the fact that these candidates, including an inactivated SARS-CoV-2 vaccine,45 have 
been shown to elicit high-titer anti-S neutralizing antibody responses. SARS-CoV-1 vaccines that 
elicit neutralizing antibodies against the SARS-CoV S protein were similarly able to protect animals 
from SARS-CoV challenge without evidence of acute lung injury and immunopathology.46 In 
addition, many SARS-CoV-2 vaccine candidates include Th1-polarizing adjuvants to minimize the 
risk of disease enhancement. Nevertheless, disease enhancement remains a theoretical risk, 
particularly after waning of antibody responses, and therefore needs to be closely monitored in human 
clinical trials of SARS-CoV-2 vaccines. 
2.6. 
Introduction to COVIVAC Vaccine 
Given the global scope of the COVID-19 pandemic, there is an urgent need for a safe and effective 
vaccine against COVID-19 that will be affordable and able to be manufactured at a sufficient scale to 
supply Vietnam and other low- and-middle-income countries. To achieve this aim, IVAC and two 
other consortium manufacturers – Government Pharmaceutical Organization (GPO), Thailand, and 
Instituto Butantan, Brazil – are independently developing an inactivated whole chimeric virion 
vaccine based on a Newcastle Disease Virus (NDV) that has been modified to also express the 
SARS-CoV-2 S protein on its surface. This technology was invented at the Icahn School of Medicine 
at Mount Sinai (ISMMS) (New York, New York, USA). Since NDV grows well in embryonated 
chicken eggs, the NDV chimeric vaccine can be manufactured using the same inexpensive egg-based 
process employed for inactivated influenza virus vaccine (IIV).47 In addition to taking advantage of 
the cost-effectiveness of the manufacturing process, an inactivated chimeric NDV vaccine propagated 
in eggs (prior to being inactivated by beta-propiolactone [BPL]) is also expected to be as safe as egg-
based IIV, which has an excellent safety profile, including in infants, pregnant women, and elderly 
adults.  
As in the case of many COVID-19 vaccines currently in development, the inactivated chimeric NDV 
vaccine expresses the ectodomain of the SARS-CoV-2 S protein – which is fused to the F protein 
transmembrane domain of NDV, resulting in abundant expression of membrane-bound S antigen (see 
Figure 1). While many candidate COVID-19 vaccines are targeting the S protein as antigen, the S 
protein expressed on the surface of the chimeric NDV virion is a much more stable construct than that 
utilized in other COVID-19 vaccines as it contains six stabilizing proline substitutions – four more 
than are introduced in the S protein antigen (S-2P) used in a number of COVID-19 candidate 
vaccines, including the Pfizer/BioNTech and Moderna vaccines. The resulting protein, called 
“HexaPro” (HXP) and developed by the University of Texas (Austin, TX, USA),48 is more 
immunogenic (>10-fold higher) than S-2P in mice (data unpublished), and also provides higher yields 
than S-2P when expressed recombinantly. As a result of these properties it is expected that significant 
dose-sparing will be possible with the COVIVAC vaccine candidate relative to other vaccine 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
25 
candidates expressing the earlier-developed S-2P antigen. Dose-sparing translates to higher 
production volumes and lower cost of vaccine. Finally it is important to note that HexaPro has also 
been shown to be more thermostable than S-2P.48 The fact that COVIVAC is expected to be 
thermally stable at 2-8 °C  is a major advantage of the vaccine over other COVID-19 candidates in 
development that will require storage at -20°C or even lower temperature.  
 
Figure 1. Electron micrograph of COVIVAC (courtesy of GPO Thailand)  
 
 
  
 
 
 
 
 
While it is likely that the whole virion COVIVAC vaccine alone will prove to be highly 
immunogenic in healthy adults due to endogenous adjuvanticity of the NDV virion, use of exogenous 
adjuvant may further increase the functional immune response to the vaccine – which may be 
important to ensure adequate protection in older adults, or possibly provide additional opportunity for 
dose-sparing. For this reason, the first part of this combined Phase 1/2 study is a first-in-human, 
Phase 1 evaluation of a 2-dose regimen of both unadjuvanted COVIVAC (at 1 µg, 3 µg, and 10 µg 
dose levels) and COVIVAC adjuvanted with CpG 1018 (at the 1 µg dose level) in healthy adults. 
CpG 1018, the adjuvant in the US-licensed HEPLISAV-B® vaccine (Dynavax Technologies 
Corporation, Emeryville, CA, USA), is a synthetic 22-mer oligodeoxynucleotide that exerts its action 
by targeting toll-like receptor 9 (TLR-9) expressed on a few key immune-cell types. When used as a 
vaccine adjuvant, CpG 1018 increases antibody concentrations to co-administered antigen, stimulates 
helper (CD4+) and cytotoxic (CD8+) T cell populations and generates robust T and B cell memory 
responses. Additionally, CpG 1018 strongly favors development of the Th1 subset of helper T cells, 
the type of helper T cell that is essential for protection from infections with viruses and intracellular 
bacteria. HEPLISAV-B was well-tolerated and shown to have an adequate safety profile in clinical 
trials in adults.49 Interim analyses of an ongoing post-marketing study of over 30,000 HEPLISAV-B 
recipients and more than 35,000 active comparator recipients have raised no safety concerns. 
2.7. 
Summary of Nonclinical Studies 
A complete summary of the COVIVAC preclinical development program is provided in the 
Investigator’s Brochure (IB).  
In brief, a pilot immunogenicity study in BALB/c mice and challenge study in golden Syrian 
hamsters (the latter evaluating multiple adjuvants including CpG 1018) have been conducted using 
bench-scale vaccine. Preliminary data show that a 2-dose vaccine regimen (21 days apart) in BALB/c 
mice and golden Syrian hamsters induces potent protective immunity, as reflected by the level of 
anti-S IgG antibody (see Figure 2), prevention of weight-loss post-challenge with SARS-CoV-2 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
26 
(hamsters, Figure 3), and the reduction of SARS-CoV-2 in the lung on Days 2 and 5 post-challenge 
(hamsters, Figure 3). This protective effect is particularly notable in hamsters, as they are known to 
develop COVID-19 lung disease much like humans.50 
Figure 2. Induction of anti-S after vaccination of mice (top) and hamsters (bottom) with NDV-HXP-S 
  
 
 
 
 
 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
27 
 
Figure 3. Data from a pilot study showing protection of golden Syrian hamsters from infection by wild-
type (WT) SARS-CoV-2. 
 
 
 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
28 
 
Additional preclinical studies (see Table 1) are described in brief below. 
Table 1. Summary of preclinical studies 
Purpose  
Species 
Groups 
Endpoints 
Challenge virus  
Institution 
Cell-mediated 
immunity 
 
Mice 
NDV only (control) 
NDV-HXP-S 
NDV-HXP -S+CpG 1018 
Anti-CoV2 S 
ELISA 
CD4, CD8 T cell, 
Th1, Th2 cytokine 
None 
ISMMS 
Protection against 
challenge with 
WT SARS-CoV-2  
Hamsters 
Mock challenge (control) 
NDV only (control) 
NDV-HXP-S 
COVIVAC +CpG 1018  
Anti-CoV2 S 
ELISA 
Weight loss x 5d, 
virus titer in lung 
USA WA1/2020, 
105 pfu, IN (non-
lethal) on D36 or 
D43 
ISMMS 
GLP-Toxicology  
Rat 
Saline control 
COVIVAC 10µg 
COVIVAC 3µg+1.5mg 
CpG 1018 
Assess potential 
local and systemic 
toxicity of vaccine 
with and without 
CpG 1018  
None 
Bioneeds India 
(GLP 
toxicology 
CRO, India) 
 
Evaluation of cell-mediated immunity in mouse study with GMP lot vaccine 
Vaccine candidates that elicit strong T-cell responses with a Th1 bias may provide durable protection 
against COVID-19, as well as minimize risk of disease enhancement. To characterize the induction of 
cell-mediated immunity by COVIVAC vaccine with and without CpG 1018, each consortium 
manufacturer’s vaccine will be evaluated in mice. Groups of mice (n=8) will be administered two 
doses of vaccine intramuscularly on day 0 and 21. Post dose 1 and 2, mice will be euthanized to 
isolate splenic T cells. T cells will be cultured overnight with peptide pools derived from S protein as 
the source of antigen stimulation, then immune-profiled to determine antigen specific CD4+ and 
CD8+ T-cell populations. The proportion of T cells secreting IFNγ or IL-5 cytokines will be 
estimated by ELISpot to assess Th polarization. 
Comparing protective efficacy of GMP lots of vaccine in hamsters  
A study is currently being conducted by ISMMS to evaluate the efficacy of each manufacturer’s 
COVIVAC vaccine with and without CpG 1018 adjuvant against wild-type (WT) SARS-CoV-2 virus 
challenge in golden Syrian hamsters. Briefly, golden Syrian hamsters of 7-8 weeks of age (n = 
8/group) will be immunized twice, three weeks apart using the GMP lot of COVIVAC vaccine from 
each manufacturer. A dose of 1 µg S antigen will be used, which corresponds to the low human dose 
planned for Phase 1. The adjuvanted vaccine group will also receive 100 µg of CpG 1018. The 
controls will be NDV vector only and mock challenged animals. Animals will be bled on Days 1, 21 
and 33. Serum samples will be tested for anti-S IgG by ELISA. On Day 35, hamsters will be 
challenged with WT SARS-CoV-2. Body weight will be measured daily from all surviving animals. 
On Days 2 or 5 post-challenge, hamsters will be euthanized, and lung tissues collected to measure 
viral titers in the upper and lower lobes of the lung.  
Repeat-dose toxicology study  

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29 
A GLP non-clinical toxicology evaluation is being conducted to evaluate COVIVAC vaccine from 
each consortium manufacturer; interim results from this study have been reported, as detailed below. 
Per guidance provided by the World Health Organization (WHO), a repeat-dose toxicology study was 
designed to test COVIVAC (including CpG 1018) at the human dose level. Since COVIVAC will be 
evaluated in clinical trials as a two-dose vaccination schedule, the toxicology study evaluated IM 
administration of three doses, following the n+1 rule.  
A total of 210 Sprague Dawley rats (105 Males and 105 Females) were randomly allocated to seven 
main groups (G) and seven recovery groups (R). Each main group consisted of 10 rats/sex and each 
recovery group consisted of 5 rats/sex. The animals allocated to group G1/G1R were administered 
0.9% normal saline. COVIVAC was administered to the other groups as shown in Table 2. 
 
 
Table 2. COVIVAC Treatment Groups (Toxicology Study) 
Antigen groups: 
Groups 
Dose 
Antigen 1  
(IVAC) 
G2/G2R 
COVIVAC 10 µg 
G5/G5R 
COVIVAC 3 µg + CpG 1.5 mg 
Antigen 2  
(Instituto Butantan) 
G3/G3R 
COVIVAC 10 µg 
G6/G6R 
COVIVAC (3 µg +  
CpG 1.5 mg 
Antigen 3  
(GPO) 
G4/G4R 
COVIVAC 10 µg 
G7/G7R 
COVIVAC 3 µg + CpG 1.5 mg 
 
  G = Group, R = Recovery group 
 
Doses were administered IM in the thigh muscle of the animals on Days 1, 15 and 29. The total 
volume administered was 0.4 mL/animal, with 0.2 mL administered to each thigh. After treatment on 
Day 29, the main group animals (G1 to G7) were sacrificed on Day 32; the animals in the recovery 
groups (G1R to G7R) were not given any treatment and observed for reversibility or persistence of 
toxic effects, and sacrificed on Day 43. Animals were observed for clinical signs of toxicity twice 
daily, with detailed clinical examination weekly; local reactions at the site of injection were evaluated 
approximately 24, 48 and 72 hours after each dose. Rectal temperature was recorded pre-treatment 
and at approximately 6 hours (± 10 min) and 24 hours (± 20 min) after each dose on Days 1, 15 and 
29. Body weight was recorded once on Day 1 prior to dosing, 3 hours post dose and on Day 2 and 
weekly thereafter. Feed consumption was measured daily. Blood was collected from all animals prior 
to treatment, on Day 3, 8 and at necropsy (Day 32 for main groups and Day 43 for recovery groups) 
from overnight-fasted animals. Urine was collected on Day 32 from main groups and on Day 43 from 
recovery groups and analysed. All animals were subjected to necropsy and detailed gross pathological 
examination at termination. Organs specified in the study plan were collected, weighed and 
preserved. Haptoglobin and alpha2-macroglobulin were analysed from main group animals (5 
rats/sex) prior to treatment (pre-dose), on Days 8 and 32 using a kit-based ELISA method. Serum 
samples collected from all rats during pre-dose, Day 32 (main groups) and Day 43 (recovery groups) 
were assessed for immunogenicity. 
Interim Results: 
All three GMP lots of vaccine drug substance from GPO, IVAC and Butantan were well tolerated in 
rats with no morbidity/mortality found in any of the groups throughout the experimental period. 
There were no clinical signs of toxicity observed during the experimental period. A few statistically 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
30 
significant variations in percent change in body weight with respect to Day 1 were noted during the 
experimental period across groups that received any of the three vaccines; these were inconsistent and 
minimal in nature and hence considered as incidental. Also, there were no concomitant variations in 
mean body weights and/or feed consumption and hence these variations in body weight not 
considered to be related to vaccine administration.  
No adverse treatment-related variations in body temperature after any dose were noted in groups of 
either sex. A few statistically significant variations of body temperature were noted during different 
measurement periods; however these were considered incidental as the variations were less than 2% 
and all the values were within 37±2°C.  No skin reactions at the site of injection were noted after any 
administration of vaccine. Haptoglobin and alpha2-macroglobulin were increased on Day 8 and Day 
32 when compared to pre-dose levels; this increase was also noted in the saline control group and 
hence considered not be related to treatment with vaccine. No adverse treatment-related changes were 
observed in hematology, coagulation, clinical chemistry and urinalysis parameters. Statistically 
significant changes were noted in hematology parameters on Days 3 and/or 8 when compared with 
pre dose sampling due to repeated blood withdrawal for clinical pathology analysis and hence not 
considered to be due to vaccine administration.  
There were no adverse treatment-related changes in fasting body weights. However, in the main 
groups, statistically significant increases in absolute and relative organ weight of the liver (G5M, 
G6M, G5F, G6F and G7F), and decreases in relative weight of ovaries (G2F, G4F, G6F and G7F), 
heart (G5F, G6F) and brain (G6F) were noted. Further data from the recovery group animals and the 
histopathology data is necessary to interpret these data.  
 
2.8. 
Study Design Rationale 
The Phase 1/2 combined study has been designed to rigorously evaluate the safety, tolerability and 
immunogenicity of COVIVAC vaccine across a range of S-antigen dose levels – one with CpG 1018 
as adjuvant – with the aim of expeditiously selecting a single candidate to advance to Phase 3 studies. 
Phase 1 will provide justification for advancement to the Phase 2 segment based on safety evaluations 
during an initial sentinel dose-escalation stage, and later an interim analysis of safety and 
immunogenicity (the latter primarily based on pseudovirus neutralization) through 28 and 14 days 
after the first and second dose, respectively. An independent Data and Safety Monitoring Board 
(DSMB) will review unblinded safety data through Day 57, and on the basis of this review provide a 
recommendation for advancing to Phase 2 (the DSMB will also be convened at any time during 
conduct of the study in the event that a study pause rule is triggered; see Section 9.3). In addition to 
this process for assessing adequate safety for advancing to Phase 2, a threshold immune response at 
Day 43 will be required for a vaccine formulation to be considered for advancement to Phase 2: 
namely, the observed seroresponse rate (defined as the percentage of subjects in a treatment group 
with at least a 4-fold rise from baseline in NT titers) will need to be at least 52% at the lower limit 
(LL) of the 95% confidence interval (CI) . Based on this criterion, there is less than 10% chance of 
incorrectly rejecting a vaccine candidate with a true seroresponse rate of 85% or higher, which is 
estimated to be the minimum response rate that would be consistent with further investment in an 
additional second-wave COVID-19 vaccine.   
If warranted, , the two optimal COVIVAC formulations will be selected for ongoing evaluation in 
Part 2 of the study based on the safety and immunogenicity results of the Phase 1 interim analysis. 
The Phase 2 segment of the study will include a sufficient number of older adults aged ≥60 (including 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
31 
those with stable chronic co-morbidities) to determine whether safety and immunogenicity of the 
vaccine may differ in this older population. It is critical that evaluation of COVIVAC in older adults 
informs the selection of the COVIVAC candidate to advance to Phase 3 studies (based on safety and 
immunogenicity through 14 days post-second vaccination in Phase 2), given the higher risk of severe 
COVID-19 in this age group, and the potential need for a higher dose level of antigen and/or use of 
adjuvant to achieve a comparable functional immune response as younger adults. Phase 2 
immunogenicity and safety data through Day 43 and Day 57, respectively, will determine the vaccine 
composition to advance to Phase 3, registration, and commercialization. Cell-mediated immunity will 
also be evaluated in a subset of subjects in the Phase 2 segment as an exploratory objective to assess 
the S protein-specific T cell response including Th polarization. An exploratory evaluation of the IgG 
immune response against the NDV HN protein will also be conducted in all Phase 2 subjects to 
generate hypotheses about the utility of administering a booster dose of COVIVAC vaccine. 
In addition to standard safety monitoring throughout the study, subjects will be evaluated for specific 
adverse event of special interest (AESI); these include potential immune-mediated medical 
conditions, which may be associated with vaccination. In addition, subjects will be closely monitored 
for adverse events associated with COVID-19 to identify, and treat if indicated, potential cases of 
COVID-19 during the trial, and to assess for possible vaccine-induced immune enhancement of 
disease. In addition to mandatory use of masks and other exposure control measures by staff and 
subjects during clinic visits, study subjects will be instructed to contact the Principal Investigator (PI) 
if they meet criteria for COVID-19 testing based on specified signs and symptoms; these criteria will 
be provided to subjects in the form of a fact sheet. 
To maintain the study blinded so that there is no bias in the ascertainment and interpretation of the 
safety and immunogenicity data, a control group will be included. While in the Phase 1 a placebo 
group was chosen as the control, it is perceived that for the phase 2 it will be practically difficult, and 
potentially ethically unacceptable to enroll subjects to receive placebo, Therefore the Phase 2 part of 
the study has been redesigned to include an active comparator group (a vaccine in use by public 
health systems in Vietnam (e.g., AstraZeneca’s). This change also allows for the possibility of 
comparing the immunogenicity of the selected doses to an emergency approved widely used around 
the world. In order to optimize comparison the number of subjects in the control arm (comparator) 
has been increased to 125 subjects, to be randomized with the two COVIVAC arms.   
2.8.1. 
Justification for Dose 
As shown above, the COVIVAC vaccine candidate elicits similar post-dose 2 titers of anti-S IgG 
antibody in mice over a 100-fold dilution (from 1 µg to 0.01 µg of total protein). The S protein of the 
vaccine content is estimated to be 10% of total protein. COVIVAC vaccine (5 µg total protein) 
administered twice to hamsters afforded excellent protection against virus challenge. These results 
suggest that relatively low doses of COVIVAC may be immunogenic in human subjects, despite the 
uncertainty of translating rodent doses to human doses. Consequently, 3 µg of S protein has been 
selected for unadjuvanted COVIVAC as the mid-dose range for clinical evaluation, with a high dose 
of 10 µg and a low dose of 1 µg. Evaluating this full dose range of COVIVAC in subjects ≥ 18 and ≥ 
60 years old will provide the necessary safety and immunogenicity data to determine whether 
increasing the dose level of COVIVAC in elderly subjects in Phase 3 may be desirable. 
Furthermore, the low dose level of COVIVAC vaccine will be evaluated ± CpG 1018 in the current 
study. CpG 1018 is approved for use in the US by the Food and Drug Administration (FDA) at a dose 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
32 
of 3 mg/ml in HEPLISAV-B. A dose of 1.5 mg/ml has been selected with COVIVAC for the 
following reasons:  
• CpG 1018 has shown a dose-dependent adjuvant effect with other vaccines. Dynavax has 
shown that 1.5 mg/ml of CpG 1018 has an acceptable adjuvant effect with protein subunit 
vaccine.51 Given that COVIVAC is an inactivated whole virion, it is expected that it will have 
intrinsic adjuvant effects that will complement the adjuvant effects of CpG 1018.  
• Advanced adjuvants, such as CpG 1018, add considerable cost per dose of vaccine. Keeping 
the level of adjuvant relatively low but still effective, will assist in controlling the cost of 
goods of the final product. 
• CpG 1018 is being tested in multiple vaccine candidates. This may put significant pressure on 
the supply/availability of CpG 1018 for approved products. Formulating COVIVAC with a 
lower dose of CpG 1018 may be beneficial when manufacturing at commercial scale.    
2.9. 
Overall Clinical Development Strategy 
The ultimate aim of developing COVIVAC vaccine for the prevention of COVID-19 is to obtain local 
registration of the vaccine in Vietnam, followed by prequalification by the WHO, with the goal of 
providing affordable access to a life-saving COVID-19 vaccine for Vietnam and other LMICs. 
Assuming this Phase 1/2 study results in advancement of an COVIVAC vaccine candidate for further 
evaluation, IVAC will likely conduct one Phase 3 trial to confirm lot-to-lot consistency and generate 
expanded safety data for that candidate. The nature of a second Phase 3 study to confirm vaccine 
effectiveness will be determined in discussions with the MoH of Vietnam. As COVID-19 vaccines 
become available and SARS-CoV-2 transmission rates decline due to population immunity and 
public health control measures, conducting placebo-controlled studies may be challenging if not 
infeasible. As a result, it may be the case that effectiveness can only be demonstrated by conducting 
an immunogenic non-inferiority trial that includes an approved comparator with a similar mechanism 
of protection.  
 
3. HYPOTHESES, OBJECTIVES AND ENDPOINTS 
3.1. 
Study Hypotheses 
Safety, Tolerability: 
• The COVIVAC vaccine (NDV-HXP-S) will have an acceptable safety profile and be well-
tolerated at all dose levels when administered as a two-dose regimen either without adjuvant (at 
1 µg, 3 µg, and 10 µg of S protein per 0.5 ml dose), or with the adjuvant CpG 1018 (at 1 µg of S 
protein per 0.5 ml dose) in the phase 1 part of the study, and at an addition dose of 6 ug dose 
in the phase 2 of the study). Safety and tolerability of the vaccine will be comparable to those 
of AstraZeneca vaccine, which will be used as an active comparator in the phase 2 study. 
Immunogenicity: 
• COVIVAC will elicit a measurable and dose-dependent neutralizing antibody response 
comparable to that induced AstraZeneca (active comparator). 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
33 
3.2. 
Study Objectives 
3.2.1. 
Primary Objectives: 
For Phase 1: 
Safety, Tolerability: 
To assess the safety and tolerability of each of four formulations of COVIVAC (at 1, 3 and 10 
µg without adjuvant; and at 1 µg with CpG 1018) after the first and second dose of a two-dose 
regimen administered at a 28-day interval to adults aged 18-59 years  
For Phase 2: 
1. Safety, Tolerability: 
1.   To assess the safety and tolerability of two selected formulations of COVIVAC, 3 µg (evaluated 
in Phase 1) and 6 µg (an intermediate dose level)  based on Phase 1 safety and immunogenicity after 
the first and second dose of a two-dose regimen administered at a 28-day interval to adults ≥ 18 
and ≥ 60 years old 
2. To assess the safety and tolerability of two selected formulations of COVIVAC (3 µg and 6 µg) 
after the first and second dose of a two-dose regimen administered at a 28-day interval to adults 
aged 18-59 years and ≥60years 
2     Immunogenicity: 
1. To assess the functional (neutralizing) humoral immune response elicited by each of two 
selected COVIVAC formulations, as measured by PNA, at baseline, 28 days after the first 
vaccination, and 14 days, 6 months and 12 months after the second vaccination, in adults ≥ 18 
and ≥ 60 years old 
2. To assess the functional (neutralizing) humoral immune response elicited by each of two 
selected COVIVAC formulations, as measured by PNA, at baseline, 28 days after the first 
vaccination, and 14 days, 6 months and 12 months after the second vaccination, in adults aged 
18-59 years and ≥60years 
3. To assess the IgG immune response elicited by each of two selected COVIVAC formulations 
against the S protein of SARS-CoV-2, as measured by ELISA, at baseline, 28 days after the first 
vaccination, and 14 days, 6 months and 12 months after the second vaccination, in adults ≥ 18 
and ≥ 60 years old 
4. To assess the IgG immune response elicited by each of two selected COVIVAC formulations 
against the S protein of SARS-CoV-2, as measured by ELISA, at baseline, 28 days after the first 
vaccination, and 14 days, 6 months and 12 months after the second vaccination, in adults aged 
18-59 years and ≥60 years 
5. To compare the immune responses observed at each dose level of COVIVAC with the corresponding 
responses observed with the AstraZeneca active comparator vaccine. 
3.2.2.  Secondary Objectives 
For Phase 1: 

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34 
1. To assess the functional (neutralizing) humoral immune response elicited by each formulation 
of NDV-HXP-S, as measured by a SARS-CoV-2 PNA, at baseline, 28 days after the first 
vaccination, and 14 days after the second vaccination (to inform the selection of two 
formulations for evaluation in Phase 2), and at 6 months and 12 months after the second 
vaccination, in adults aged 18-59 years  
2. To assess the IgG immune response elicited by each formulation of COVIVAC against the S 
protein of SARS-CoV-2, as measured by ELISA, at baseline, 28 days after the first vaccination, 
and 14 days, 6 months and 12 months after the second vaccination, in adults aged 18-59 years  
3.2.3. 
Exploratory Objectives: 
Immunogenicity: 
For Phase 2: 
1. To assess the S protein-specific T cell response elicited by each of two selected COVIVAC 
formulations, as measured by ELISpot, at baseline, and 6 months after the second vaccination, in 
adults aged 18-59 and ≥60 years old (subset of subjects) 
2. To assess the S protein-specific T cell response elicited by each of two selected COVIVAC 
formulations, as measured by ELISpot, at baseline, and 14 days and 6 months after the second 
vaccination, in adults aged 18-59 years and ≥60 years (subset of subjects in each age stratum) 
Note: other exploratory studies to further characterize the immune response to COVIVAC may be 
conducted in Phase 1 or Phase 2. This includes evaluation of the functional response to COVIVAC as 
measured by a wild-type neutralization assay, which will be conducted if a collaboration for 
performing the assay is established.  The collaborator for evaluation of the cell-mediated immune 
response to COVIVAC in Phase 2 is also yet to be determined. 
3.3. 
Study Endpoints 
3.3.1. 
Primary Endpoints: 
Safety, Tolerability: 
• 
Number and severity of solicited local and systemic AEs during the first 7 days after each 
vaccination  
• 
Number, severity, and relatedness of clinically significant hematological and biochemical 
measurements at 7 days post each vaccination  
• 
Number, severity and relatedness of all unsolicited AEs during the first 28 days after each 
vaccination  
• 
Number, severity and relatedness of SAEs throughout the entire study period 
• 
Number, severity and relatedness of MAAEs throughout the entire study period 
• 
Number, severity and relatedness of AESI throughout the entire study period, including AESI 
relevant to COVID-19, and potential immune-mediated medical conditions (PIMMC)  
3.3.2. 
Secondary Endpoints: 

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35 
Immunogenicity: 
For Secondary Objective 1 (Phase 1), and primary Objectives (Phase 2): 
• NT50 and NT80 (phase 1 only) GMT against SARS-CoV-2 pseudovirus at 28 days after the first 
vaccination (phase 1 only), and 14 days and 6 months after the second vaccination in subjects 
who are anti-S IgG seronegative at baseline 
• GMFR (from baseline) in NT50 and NT80 (phase 1 only) against SARS-CoV-2 pseudovirus at 
28 days after the first vaccination(phase 1 only), and 14 days and 6 months after the second 
vaccination 
• Percentage of subjects with NT50 and NT80 (phase 1 only) seroresponses against SARS-CoV-2 
pseudovirus as defined by (1) a ≥ 4-fold increase from baseline, and (2) a ≥ 10-fold increase 
from baseline at 28 days after the first vaccination (phase 1 only), and 14 days and 6 months 
after the second vaccination 
 
For Secondary Objective 2 (Phase 1), and Objectives 3 and 4 (Phase 2):  
• Anti-S IgG GMT at 28 days after the first vaccination (phase 1 only), and 14 days and 6 
months\ after the second vaccination in subjects who are anti-S IgG seronegative at baseline 
• GMFR (from baseline) in anti-S IgG GMT at 28 days after the first vaccination (phase 1 only), 
and 14 days and 6 months after the second vaccination 
• Percentage of subjects with seroresponses in anti-S IgG titer as defined by (1) a ≥ 4-fold 
increase from baseline, and (2) a ≥ 10-fold increase from baseline, at 28 days after the first 
vaccination (phase 1 only), and 14 days and 6 months after the second vaccination 
3.3.3. 
Exploratory Endpoints: 
Immunogenicity 
For Exploratory Objectives 1 and 2 (Phase 2): 
• Magnitude, functionality, and Th polarization of S protein-specific T cells relative to baseline at 
14 days and 6 months after the second vaccination 
 
Note: In this protocol one month in this study context is defined as 4 weeks or 28 days; then 6 
months means 24 weeks or 168 days, and 12 months means 48 weeks or 336 days. 
 
4. 
STUDY DESIGN 
This prospective, single-center, randomized, placebo-controlled (phase 1) and active-controlled 
(phase 2), observer-blind Phase 1/2 study includes two separate parts. The treatment groups to be 
evaluated in each part of the study (and their corresponding sample size) are presented in Table 3. 
 
 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
36 
  Table 3.  Treatment Groups 
 
 
 
 
 
 
 
 
 
Part 1 is a first-in-human, Phase 1 study designed to evaluate the safety, tolerability, and 
immunogenicity of the COVIVAC vaccine at three different dose levels (1, 3, and 10 µg) without 
adjuvant, and at one dose level (1 µg) with the adjuvant CpG 1018, in a total of 120 subjects aged 18-
59 years. Eligible subjects will be randomly assigned to receive study vaccine or placebo as an IM 
injection in the deltoid muscle at Visit [V]1 as part of one of four sequential groups of escalating 
antigen dose level or added adjuvant. Each group will be divided into two sequential subgroups, a 
sentinel subgroup (n=6) and a larger subgroup (n=24) that includes the remaining subjects to be 
evaluated at that dose level (or for that formulation in the case of the one adjuvanted treatment 
group). Initially, a sentinel subgroup of 6 subjects will be randomized to receive COVIVAC 1 µg or 
placebo in a 5:1 ratio (subjects within a sentinel subgroup will receive the first injection only after 
immediate reactogenicity assessments of the prior subject in the subgroup are completed). Sentinel 
subjects will be monitored for reactogenicity and safety through Day 8 (Visit 2), including for the 
initial 24 hours post-injection in clinic. If the PSRT has no safety concerns based on blinded review 
of all safety data, including clinical laboratory results, through Visit 2, the second subgroup of 24 
subjects will be randomized to receive COVIVAC 1 µg or placebo at the same ratio; on the same day, 
the sentinel subgroup  (n=6) for the second dose level to be evaluated (COVIVAC 3 µg) can be 
randomized to receive study vaccine or placebo in a 5:1 ratio, and so on for the subsequent dose level 
and formulation (see Table 4).   
 
 
Phase 
Group 
Sample Size 
Study Product 
1 
1 
20 
Placebo 
2 
25 
COVIVAC 1 µg 
3 
25 
COVIVAC 3 µg 
4 
25 
COVIVAC 10 ug 
5 
25 
COVIVAC 1 µg + CpG1018 1.5 mg 
2 
1 
125 
AstraZeneca 
2 
125 
COVIVAC 3 µg 
3 
125 
COVIVAC 6 µg 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
37 
Table 4.  Phase 1 Dose Escalation Steps 
 
V1 = Visit 1 (Day 1) 
V2 = Visit 2 (Day 8) 
PSRT = Protocol Safety Review Team meeting 
The PSRT will review blinded safety, reactogenicity and clinical laboratory data accrued on a weekly 
basis until D43 of the last subject in each phase of the study, then at least once monthly until the end 
of the study. Subjects will receive 2 doses of assigned IP on D1 and D29 (V1 and V3), and be 
assessed in clinic for safety and reactogenicity at 7 days after each vaccination (V2 and V4, [phase 1 
only]), for safety at 28 days after the second vaccination (V6), and for safety and immunogenicity 
assessments at baseline (V1), 28 days after the first vaccination (V3) and 14, 168 and 336 days after 
the second vaccination (V5, V7, and V8, EOS Visit). 
 
An interim analysis of Phase 1 data conducted after the last subject last visit for V6 (D57) will serve 
as the basis for decisions about down-selection and advancing to Part 2 of the study (Phase 2). Down 
selection and advancement to Part 2 (Phase 2) will be based on the following parameters: 
• Post-dose 2 immunogenicity results at the aggregate treatment level  
o A threshold immune response at Day 43 will be required: the observed seroresponse rate in a 
treatment group (defined as the percentage of subjects with at least a 4-fold rise from 
baseline in 80% neutralizing antibody titers) will need to be ≥52% at the LL of the 95% CI 
for that treatment (vaccine formulation) to be considered for advancement to Phase 2. 
• Post-dose 1 and post dose 2 safety results including all solicited and unsolicited adverse events, 
serious adverse events, and clinical laboratory results. 
 
The following process will be followed for the decision about down selection and advancing Part 2 
(Phase 2):  
• The DSMB will review the unblinded safety data and provide a recommendation to the Sponsor 
on whether the safety profile is acceptable for advancing a formulation to Phase 2.  
• The Sponsor will review the DSMB recommendation in conjunction with the immunogenicity 
data and select two formulations to advance to Phase 2. 
 
Subgroup 
Escalation Steps  
Dose  1µg & 
Placebo (5+1) 
V1 
V2 
 
  
 
 
 
 
 
 
 
 
 
 
 
Dose  1µg & 
Placebo (20+4) 
 
V1 
V2 
 
 
 
 
 
 
Dose  3µg & 
Placebo (5+1) 
V1 
V2 
 
 
 
 
 
 
Dose  3µg & 
Placebo (20+4) 
 
 
 
V1 
V2 
 
 
 
 
Dose  10µg & 
Placebo (5+1) 
 
 
 
V1 
V2 
 
 
 
 
Dose  10µg & 
Placebo (20+4) 
 
 
 
 
 
V1 
V2 
 
 
Dose  1µg+CpG 
& Placebo (5+1) 
 
 
 
 
 
V1 
V2 
 
 
Dose  1µg+CpG 
& Placebo (20+4) 
 
 
 
 
 
 
 
V1 
V2 
Review 
 
 
PSRT 
 
 
PSRT 
 
 
PSRT 
 
 
PSRT 
 
 

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38 
o If multiple formulations achieve the threshold immune response (as well as have an adequate 
safety and tolerability profile per the DSMB), the Sponsor will select two formulations to 
advance to Phase 2 based on consideration of such factors as the relative functional 
immunogenicity of these formulations, opportunity for dose sparing, and opportunity to limit 
cost and possible supply constraints associated with use of the CpG adjuvant.   
• The selection and recommendation to advance to Phase 2 along with the interim report will be 
jointly reviewed by NIHE’s IRB and MoH prior to Phase 2 enrollment.  
 
In Part 2 of this Phase 1/2 study, 375 adults ≥ 18 and ≥ 60 years old will be randomized (1:1:1) to 
placebo, or one of two selected formulations of COVIVAC, 3 µg (evaluated in Phase 1) and 6 µg (an 
intermediate dose level based on the phase 1 interim analysis). At least one-third of the subjects in 
Phase 2 will be aged ≥60 years to ensure that adequate safety and immune data will be available from 
older and elderly adults to inform the selection of the COVIVAC formulation to advance to Phase 3 
studies. The Phase 2 cohort will follow the same visit schedule, and undergo the same procedures and 
assessments, as in Phase 1. In addition, as exploratory objectives, the anti-NDV HN IgG response 
will be assessed at V1, V3, V5, and V7 in all subjects in phase 1 if a laboratory is determined as 
capable of doing this test , and 36 subjects (equally distributed between the two age strata) will be 
randomly selected in a 1:1:1 ratio to provide additional blood at V1, V5 and V7 to be used to isolate 
PBMCs for assessment of T-cell-mediated immunity. Other exploratory assays to characterize the 
immune response to COVIVAC may also be performed. 
An interim analysis of Phase 2 data will be conducted after the last subject of the Phase 2 cohort 
completes V6 (D57) as the basis for selecting the optimal formulation of COVIVAC to advance to 
Phase 3 studies. As was the case for the Phase 1 interim analysis at the same timepoint, the data 
generated will include unblinded post-dose 1 and dose 2 safety results for review by the DSMB, and 
immunogenicity results aggregated by treatment group for review by the Sponsor. The DSMB will 
consider all accumulated safety data from both phases of the study prior to making any 
recommendation to the Sponsor that it not advance a formulation based on safety concerns. The 
Sponsor will ultimately select the formulation to advance to Phase 3 that, in addition to having been 
judged by the DSMB to have an adequate safety and tolerability profile, is optimal based on relative 
functional immunogenicity and other programmatic considerations such as those noted above. 
 
5. STUDY POPULATION 
5.1. 
Study Population 
The study population will consist of eligible, Vietnamese male and female adults aged 18->60 years 
old, inclusive. 
5.2. 
Clinical Trial Site  
• Phase 1: 
Phase 1 of the study will be conducted at Hanoi Medical University (HMU), where facilities are 
available to conduct intensive in-clinic safety monitoring for 24 hours after the 1st study product 
administration, and for 4 hours after the 2nd study product administration. Hanoi Medical 
University is experienced in the conduct of clinical trials. Study subjects in Phase 1 will be 
recruited via advertisement in mass media, and websites of NIHE, HMU and IVAC; volunteers 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
39 
will contact the study team for registration. The advertisement materials will be reviewed by 
relevant Ethics Committees before going live. 
As of 6 January 2021, Hanoi has recorded 198 COVID-19 cases. For approximately the last 4 
months, there has been no case of COVID-19 in Vietnam resulting from community transmission; 
new cases have been imported from outside of Vietnam and quarantined upon arrival. As a result 
exposure to SARS-CoV-2 is likely to be limited during conduct of the study, thus limiting 
censoring of subjects from immunogenicity analyses requiring baseline seronegativity. 
• Phase 2: 
Phase 2 of the study will be conducted at Vu Thu district health center and commune health 
centers of Vu Thu district, Thai Binh province in Vietnam. National Institute of Hygiene and 
Epidemiology (NIHE) will collaborate with staff of the commune health centers, district health 
center, district hospital, as well as the staff of the Provincial Center for Disease Control for 
conduct of this study. Thai Binh CDC and district health center have collaborated with NIHE for 
several vaccine clinical trials funded by international sponsors and monitored by contract research 
organizations (CROs).  
According to the health system in Vietnam, the district hospitals and their corresponding district 
health centers, the provincial general hospital, and the CDC are all managed by the Provincial 
Health Services; so it is straightforward to coordinate care among them should a serious adverse 
event occur. The staff of commune and district health centers conduct routine vaccinations in the 
community and have the capacity to handle serious vaccine reactions. The district hospitals also 
have good capacity in terms of both personnel and equipment to provide medical care, including 
emergency care. The district health center is only approximately 7 kilometers (10 minute drive) 
from provincial general hospitals that would be engaged to manage higher grade and serious 
adverse events requiring hospitalization or referred events requiring consultation with a specialist. 
This will assure rapid patient transport and referral to tertiary care hospitals at provincial levels in 
case such referral is necessary. The study documents will be stored at the provincial CDC where 
data entry will occur, and will be moved to the district health center when a study visit is 
occurring there. The study samples will also be stored at the provincial CDC lab. The study team 
will recruit subjects for this study from the communes around the Vu Thu district health center. 
Subjects will be seen at the Vu Thu district health center for scheduled study visits, and receive 
routine medical care at Vu Thu district hospital. Subjects will be encouraged to contact the study 
team if they have any new onset medical conditions, medically attended events, notable signs 
and/or symptoms of COVID-19, or other concerns during their period of enrollment in the study 
to ensure all safety data are collected in a complete, accurate and timely manner. 
As of 6 January 2020, there has been no confirmed case of COVID-19 in the Vu Thu district. In 
daily life, people living in Vu Thu district do not often have contact with people outside of their 
community, as travel outside the district – and migration into the district – is rare. This is 
expected to facilitate compliance with study visits and safety monitoring generally. Also, 
exposure to SARS-CoV-2 is likely to be very limited during conduct of the study, thus limiting 
censoring of subjects from immunogenicity analyses requiring baseline seronegativity.  
Regardless of estimated exposure risk, HMU and Vu Thu district health center will follow the 
policies and procedures implemented by Ministry of Health to minimize risk of SARS-CoV-2 
transmission at these facilities, including mandatory use of masks by all staff, social distancing, 

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40 
and frequent handwashing/sanitizing. This policy will be extended to include study subjects (and 
prospective subjects) during clinic visits, and will be strictly enforced. Study subjects will also be 
instructed on how to minimize risk of exposure to SARS-CoV-2 while outside of the study clinic, 
including during transit to and from study visits at HMU and Vu Thu district health center. 
As of 22/06/2021 there have been still Covid-19 transmission cases in community and all study 
participants had completed the V6/D57 visit. In Vu Thu district- Thai Binh province, so far there 
still have been no Covid-19 transmission case detected in the community. However, the study 
team would still comply with all preventive measures mentions above while conducting the study 
procedures for phase 2 and 2 remaining visit of V7/D197 and V8/D365 of the phase 1. 
Prospective subjects who are consented to participate (i.e., enrolled) in this Phase 1/2 study will only be 
eligible for randomization if, during screening, they meet all of the inclusion criteria, and none of the 
exclusion criteria, as follows: 
5.3. 
Inclusion Criteria 
Phase 1 Only: 
1. Adult 18 through 59 years of age inclusive at the time of randomization. 
2. Healthy, as defined by absence of clinically significant medical condition, either acute or chronic, 
as determined by medical history, physical examination, screening laboratory test results, and 
clinical assessment of the investigator. 
Phase 2 Only: 
1. Adult ≥ 18 years old inclusive at the time of randomization. 
2. Having no clinically significant acute medical condition, and no chronic medical condition that 
has not been controlled within 90 days of randomization, as determined by medical history, 
physical examination, screening laboratory test results, and clinical assessment of the investigator. 
Both Phase 1 and Phase 2: 
3. Has provided written informed consent prior to performance of any study-specific procedure. 
4. Has a body mass index (BMI) of 17 to 40 kg/m2, inclusive, at screening. 
5. Resides in study site area and is able and willing to adhere to all protocol visits and procedures. 
6. If a woman is of childbearing potential age, must not be breastfeeding or be pregnant (based on a 
negative urine pregnancy test at screening and during the 24 hours prior to receipt of the first dose 
of IP), must plan to avoid pregnancy for at least 28 days after the last dose of IP, and be willing to 
use an adequate method of contraception consistently and have a repeated pregnancy test prior to 
the second (last) dose of IP. 
5.4. 
Exclusion Criteria 
1. Use of any investigational medicinal product within 90 days prior to randomization or planned 
use of such a product during the period of study participation. 
2. History of administration of any non-study vaccine within 28 days prior to administration of study 
vaccine or planned vaccination within 3 months after enrolment. 

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41 
Note: receipt of any COVID-19 vaccine that is licensed or granted Emergency Use Authorization 
in Vietnam during the course of study participation is not exclusionary if administered after Visit 
5. 
3. Previous receipt of investigational vaccine for SARS or MERS, or any investigational or licensed 
vaccine that may have an impact on interpretation of the trial results 
4. History of hypersensitivity reaction to any prior vaccination or known hypersensitivity to any 
component of the study vaccine 
5. History of egg or chicken allergy 
6. History of angioedema 
7. History of anaphylaxis (≥ grade 2) 
8. Acute illness (moderate or severe) and/or fever (body temperature measured orally ≥38°C) 
9. Any abnormal vital sign deemed clinically relevant by the PI 
10. Abnormality in screening laboratory test deemed exclusionary by the PI in consultation with the 
Sponsor 
11. A positive serologic test for hepatitis B (HBsAg) or hepatitis C (HCV Ab) (phase 1 only) 
12. History of confirmed HIV  
13. History of laboratory-confirmed COVID-19 
14. History of malignancy, excluding non-melanoma skin and cervical carcinoma in situ 
15. Any confirmed or suspected immunosuppressive or immunodeficient state 
16. Administration of immunoglobulin or any blood product within 90 days prior to first study 
injection or planned administration during the study period. 
17. Administration of any long-acting immune-modifying drugs (e.g., infliximab or rituximab) or the 
chronic administration (defined as more than 14 days) of immunosuppressants within six months 
prior to first study injection, or planned administration during the study period (includes systemic 
corticosteroids at doses equivalent to ≥ 0.5 mg/kg/day of prednisone; the use of topical steroids 
including inhaled and intranasal steroids is permitted). 
18. History of known disturbance of coagulation or blood disorder that could cause anemia or excess 
bleeding. (e.g, thalassemia, coagulation factor deficiencies). 
19. Recent history (within the past year) or signs of alcohol or substance abuse. 
20. Any medical, psychiatric or behavior condition that in the opinion of the PI may interfere with the 
study objectives, pose a risk to the subject, or prevent the subject from completing the study 
follow-up.  
21. Employee of any person employed by the Sponsor, the contract research organization (CRO), the 
PI, study site personnel, or site. 
 
Note: specific exclusion criteria (e.g., ≥Grade 2 acute illness, or abnormal vital sign deemed 
clinically relevant by the PI/designee) will be reassessed at both vaccination visits. Any subject who 
cannot be vaccinated due to an acute abnormality assessed at a vaccination visit (Visit 1 or Visit 3) 

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42 
may return once the acute issue has resolved, if deemed appropriate by the PI/designee. A minimum 
of 48 hours must have passed after a documented fever before a subject can be vaccinated. This safety 
requirement will not be deemed a protocol deviation should the visit fall outside the vaccination 
window; however, it will be encouraged to maintain the vaccination window whenever possible in 
these situations. Clinical laboratory test results and vital signs used to determine subject eligibility 
will be those obtained at screening. These tests may be repeated once if deemed appropriate by the 
investigator and determined to be due to a transient condition that has resolved. In addition, a test 
may also be repeated for test results determined to be spurious by the investigator (e.g., following 
improper specimen collection). The last measurement will be taken as the baseline for purposes of 
analysis. 
5.5. 
Screen Failures 
Prospective subjects who are enrolled in the study, and who subsequently do not meet one or more 
criteria required for participation in the study during the screening period, are considered screen 
failures. Any individual deemed a screen failure may not be rescreened. All screen failures will be 
recorded in the Case Report Form (CRF). Any individual deemed a screen failure due to a previously 
undiagnosed medical condition will be provided with appropriate referral within the health care 
system. 
 
6. STUDY PRODUCT 
6.1. 
Product Descriptions 
COVIVAC is an inactivated NDV chimera expressing a trimeric pre-fusion form of the SARS-CoV-2 
S protein that contains six proline mutations (HexaPro). The vaccine is a clear and slightly opalescent 
liquid.  
All study vaccine products to be administered on a given day (based on the study stage) will be 
formulated separately by the assigned site staff under aseptic conditions at the start of the clinic day. 
A detailed mixing procedure will be provided in the Pharmacy Manual or SOP for study product 
preparation. Each vaccine product will be formulated by filling a 4 ml (4R) [with the height of 46 mm 
and diameter of 16/1 mm] USP Type I glass vial with bulk drug substance, bulk adjuvant (if indicated 
based on formulation) and phosphate-buffered saline (PBS) to allow for five 0.5 ml doses per vial, as 
well as sufficient residual volume for possible dose verification. Each vial label will include the 
following information: name of the medicinal product, composition, fill volume, route of 
administration, lot number, manufacturing date,  storage condition, and a cautionary statement (“For 
Clinical Trial Use Only”). 
The placebo control for the Phase 1 part of the study is PBS (pH 7.2), manufactured by IVAC and 
tested by National Institute for Control of Vaccines and Biological (NICBV). 
For the phase 2: study vaccine of 2 selected dose levels is already prepared and filled with the volume 
of 6 ml in 10 ml vials. Each vial includes 10 doses of 0.5 ml. The remaining volume of vials after being 
drawn will be returned to the sponsor. Active control is AstraZeneca vaccine which has been granted 
the EUA and has been used widely in Vietnam. 
6.2. 
Stability and Storage 

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43 
The temperature of bulk COVIVAC drug substance and CpG 1018 will be monitored during 
shipment to and storage at the clinical site to ensure that temperature deviations do not occur. The 
temperature of shipments will be monitored throughout transit using a continuous temperature 
monitoring system. Vaccine and adjuvant will not be used until their temperature throughout transit 
has been confirmed to be within acceptable limits. Upon receipt at clinical trial center of NIHE, final 
and bulk COVIVAC vaccine, CpG 1018 adjuvant, and PBS will be stored at 2°C to 8°C in a 
dedicated refrigerator that is safe, locked, and not accessible to unauthorized staff –. The refrigerator 
will be under continuous temperature monitoring with maintenance of daily temperature logs and 
connected to a power source with a reliable back-up system. COVIVAC vaccine, CpG 1018 and PBS 
must not be frozen. 
 
It is the responsibility of designated unblinded site staff to ensure that study products have not been 
exposed to temperatures outside the allowed range during transport or storage at HMU and Vu Thu 
district health center prior to being dispensed for vaccination. Should there be a deviation outside the 
allowed temperature range, the affected vaccine will be quarantined. The temperature deviation will 
be reported to the Sponsor and CRO within 24 hours of awareness who will advise the unblinded 
investigator team of the action to be taken based on the magnitude and duration of the temperature 
deviation. All drug accountability procedures will be documented and are the responsibility of the 
unblinded study staff. 
 
6.3. 
Preparation and Administration 
A limited number of appropriately trained, unblinded study staff, including the site pharmacist, will 
be responsible for preparing study products (in accordance with the randomly determined 
assignment), administering the study vaccine, and handling all drug accountability procedures. These 
personnel will not participate in the other aspects of the clinical trial, to help ensure the integrity of 
the blind at the site. The unblinded staff will not reveal subjects’ randomization assignments to 
subjects, or staff associated with the Sponsor, CRO, or site.  
Unblinded staff will retrieve a subject’s randomization assignment via secure Interactive Web 
Response System (IWRS) or alternative approach (randomization envelope) after being informed by 
the PI or designee that a subject is eligible for randomization. They will prepare the 0.5 ml dose of 
study product based on the subject’s randomization assignment in a setting distinct from the clinic 
staff. Since COVIVAC vaccine may appear opalescent, the syringe barrels of study product will be 
masked to maintain the observer-blind study design. A total of five doses of study product (phase 1) 
and ten 10 doses of study product (phase 2) may be drawn from each vial of formulated study vaccine 
prepared for clinic on the same day; however, in no circumstance may a dose be prepared and 
administered more than 6 hours after a vial of study product has been formulated (the vials will be 
stored between 2°C and 8°C during this interval). To be prepared for the highest level of possible 
medical risk, vaccination will take place in a clinical setting in which there is immediate access to the 
medical personnel, equipment, and medications required for emergency resuscitation. 
Since COVIVAC vaccine is a suspension, study vaccine must be shaken gently immediately prior to 
use, in order to obtain a uniform homogenous suspension (clear to opalescent in color). Inspection of 
each vial will occur immediately prior to use. If a vial or its contents appear unusual in any way, the 
vial will not be used, and procedures detailed in the Pharmacy Manual for documentation and 
disposal will be followed.  

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44 
COVIVAC vaccine, PBS placebo and the active comparator vaccine should be administered as an IM 
injection into the mid-deltoid muscle of the subject’s non-dominant arm. Should the non-dominant 
arm not be acceptable based on clinical assessment (e.g., local infection or pre-existing swelling or as 
requested by subjects) the dominant arm may be used and the reason for the change documented. The 
arm of injection should be opposite to the arm of bleeding except certain cases (for example: the 
intended injection site is abnormal or injured, or as requested by subjects). The site at which study 
vaccine is administered will be documented in the CRF for all subjects. A detailed account of 
procedures related to preparation and administration of study vaccine will be included in the SOP for 
study product preparation. 
 
For the phase 2: 0.5 ml dose of study vaccine or placebo will be drawn from vials already prepared and 
filled by sponsor. 
6.4. 
Accountability and Disposal 
The site pharmacist is required to maintain complete records of all study products received from the 
Sponsor and will be responsible for maintaining an accurate record of the randomization codes, 
inventory, and an accountability record of vaccine and placebo supplies for the study. The site 
pharmacist will also be responsible for ensuring the security of these documents. All used vials of 
study product will be stored in a dedicated space that is accessible only to the unblinded site staff and 
the unblinded CRO monitor, who is responsible for the monitoring and final accountability of all 
study products. Partially used vials after the completion of a clinic day will not be used for human 
administration or for any other investigational purpose. After final drug accountability is completed, 
all used and unused study products must be disposed of according to the Sponsor’s instructions. Due 
to the need to maintain blinding, no drug accountability records will be sent to the Sponsor or 
included in the trial master file (TMF) until after database lock. 
 
 
 
7. STUDY PROCEDURES 
7.1. 
Recruitment 
Details on recruitment and retention of subjects will be outlined in a Recruitment and Retention Plan 
prior to study initiation. 
In Phase 1 of the study, subjects will be recruited via advertisement in mass media, and websites of 
NIHE, HMU and IVAC; volunteers will contact study team for registration. The advertisement 
materials will be reviewed by relevant Ethics Committees before going live. Potential subjects who 
are interested in study participation will be invited to Hanoi Medical University to attend an ICF 
meeting and then a one-to-one consultation with the investigator to address questions and concerns 
before being consented and signing the ICF. 
 In Phase 2 of the study, the study staff will work together with the appropriate district health and 
commune health staff to recruit study participants, using IRB-approved recruitment strategies.  
The commune staff will work with population collaborators/village health workers to develop a list of 
potential study participants based on the existing Village Population Register Books. After that they 

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45 
will go household to household to introduce the study and eligibility criteria to potential study 
participants using information from the “Information Sheet” of the consent document.  
Once a potential study participant confirms their interest, they will be invited to Vu Thu District 
Hospital to attend an ICF meeting and participate in screening if they are consented. 
At the ICF meeting, there will be an information session presented by the PI/designee to provide all 
necessary information related to the study. After the information session, each potential participant 
will have a one-and-one meeting with one of the assigned study investigators to further discuss the 
trial and ask any questions they may have. The investigator will assess the potential participant’s 
understanding of key aspects of the study, such as the voluntary nature of study participation and 
potential risks and benefits, using an assessment of understanding. The investigator will review with 
the participant any answers they did not understand in order to clarify any misunderstandings. Only 
after that, if participant provided consent and signed the ICF, can the screening procedures be started. 
The study staff will follow inclusion/exclusion criteria to determine eligibility. Screening will be 
conducted on all people who have signed the study consent, and their results will be reviewed with 
them, regardless of eligibility.  
7.1.1. 
Initial and Continuing Informed Consent 
Informed consent is the process of ensuring that study subjects fully understand the purpose of the 
study and what will and may happen to them while participating in the study. Initial written informed 
consent is required before any study procedures are performed. The informed consent process 
continues throughout the study. If any new information becomes available that, in the judgement of 
the PI or Sponsor, may affect subjects’ decision to continue in the trial, such information will be 
shared with subjects, who may be asked to sign a new consent form. 
7.2. 
Study Visits 
Procedures to be performed at each study visit are shown in Table 5 as follows: 
 

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46 
Table 5. Schedule of Study Visits and Procedures – Phase 1 and Phase 2 
VISIT 
Screen 
V1 
V2 
V3 
V4k 
V5 
V6 
V7 
Study Day 
(allowed window in days) 
-28 to 1 
1 
8 
(+3) 
29 
(+3) 
36  
(+3) 
43 
(+3) 
57 
(+7) 
197 
(+14) 
Informed consent  
✓ 
 
 
 
 
 
 
 
Demographics 
✓ 
 
 
 
 
 
 
 
Medical History 
✓ 
 
 
 
 
 
 
 
Concomitant medicationsA 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Eligibility check 
✓ 
 
 
~ 
 
 
 
 
Vital signs  
✓ 
✓^✓ 
✓ 
✓^✓ 
✓ 
✓ 
✓ 
✓ 
Complete physical exam 
✓ 
 
 
 
 
 
 
 
Targeted physical examB 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Clinical chemistryC 
✓ 
 
✓ 
 
✓ 
 
 
 
HematologyD 
✓ 
 
✓ 
 
✓ 
 
 
 
Viral serology testsE 
✓ 
 
 
 
 
 
 
 
Urine pregnancy testF 
✓ 
✓ 
 
✓ 
 
 
 
 
Unsolicited AEsG 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Concomitant medicationsH 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Randomization 
 
✓ 
 
~ 
 
 
 
 
Blood for humoral immunity 
 
✓ 
 
✓* 
 
✓ 
 
✓ 
Blood for CMII 
 
✓ 
 
 
 
✓ 
 
✓ 
Administer study product 
 
✓ 
 
✓ 
 
 
 
 
Observation/solicited AEs 
 
✓ 
 
✓ 
 
 
 
 
Provide Diary Card 
 
✓ 
 
✓ 
 
 
 
 
Review Diary Card 
 
 
✓ 
 
✓  
✓ k 
 
 
Exit study 
 
 
 
 
 
 
 
 
Blood volumes (mL): 
 Safety laboratory tests  (Phase 1 only) 
4 
 
4 
4 
 
 
 HBV and HCV screening 
2 
 
0 
0 
 
 
     Humoral immunity    
 
10 
 
10 
 
10 
 
10 
    Cell-mediated immunity 
 
16 
 
 
 
16 
 
16 
~ Confirmation  
^ Evaluations will be conducted twice – before and after vaccination 
* Only in Phase 1 
A After Visit 6, only medications associated with an AESI, MAAE or SAE will be recorded. 
B Targeted PE will be conducted only in the event of new symptom, sign or, until Visit 6, any new AE; or, after Visit 
 6, any new AESI, MAAE or SAE. 
C Serum creatinine, ALT, AST, total bilirubin; only in Phase 1. 
D WBC count, hemoglobin, platelets; only in Phase 1.  
E HBsAg, HCV Ab, only in Phase 1. 
F Women of childbearing potential (WOCBP) only 
G After Visit 6, only AESI, MAAEs, and SAEs will be recorded. 
       H After Visit 6, only concomitant medications associated with a newly reported MAAE or SAE will be recorded 
I Only in subset of subjects in Phase 2 

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47 
k In Phase 1 the diary card will be reviewed at Visit 4 (Day 36). In Phase 2, study staff will make a phone call/home visit to remind 
subjects to complete the diary card at Visit 4 (Day 36), and the diary card will be collected and reviewed at Visit 5 (Day 43) (2 
weeks after vaccination) 
m for phase 1 only, V8/D365 will not be conducted in the phase 2.. 
 
Note: The study dates of follow-up visits after the V3/D29 visit will be adjusted according to the actual date of the 
V3/D29 visit. 
7.2.1. 
Screening (Day -42 to Day 1) 
Once informed consent has been documented, the prospective subject will be considered to be 
enrolled in the trial and may be screened to determine study eligibility. All inclusion/exclusion 
criteria must be assessed from data obtained within the screening period, unless otherwise specified in 
the eligibility criteria. After informed consent has been obtained, the following screening procedures 
will be performed: 
1. Subject identification (ID)/screening number will be assigned. 
2. The following information will be obtained from the subject: 
a. Demographic and contact information, including home address, telephone number(s), 
and email address 
b. Complete medical history of relevance to study eligibility  
c. History of medication use in the past 30 days, and of medications taken that are of 
specific relevance to study eligibility (e.g., immunosuppressive medications) 
d. Vaccination history (collecting only vaccines administered within 1 years from the 
screening visit) 
3. Height and weight will be measured, BMI calculation. 
4. A full physical examination (PE) will be performed, including vital signs (temperature, pulse 
rate, and respiratory rate) and assessment of the major organ systems.  
5. A urine pregnancy test will be performed for all women of childbearing potential age 
(WOCBP). 
6. Venous blood samples (approximately 6 mL only in phase 1) will be obtained (non fasting) 
for clinical laboratory tests, as follows: 
a. White blood cell (WBC) count, hemoglobin (Hgb), platelets (Plt) 
b. Serum creatinine, alanine transaminase (ALT), aspartate transaminase (AST), total 
bilirubin (t bili) 
c. HBsAg, HCV Ab 
Grade 1 vital sign and safety laboratory abnormalities (see Appendix 2 and 3) will not be considered 
to be exclusionary at screening nor an AE for the study unless judged to be clinically significant by 
the PI/designee, in consultation with the Sponsor. Prospective subjects may return for repeat 
assessments once during the screening period to be reassessed for eligibility. The last measurement 
will be taken as the baseline for purposes of analysis. The PI/designee will use good clinical judgment 
in considering a prospective subject’s overall eligibility. 
7.2.2. 
Visit 1 (Day 1) 

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At Visit 1, the following procedures will be performed: 
1. 
Subject ID, addresses and telephone number(s) will be confirmed. 
2. 
A urine pregnancy test will be performed for all WOCBP. 
3. 
Unsolicited AEs will be recorded, including assessment of severity and outcome. Ongoing 
unsolicited AEs will be reviewed. 
4. 
Concomitant medications will be recorded. 
5. 
Vital signs will be measured prior to dosing. 
6. 
Targeted PE will be performed to evaluate any symptom, sign or reported AE, and to confirm 
absence of exclusionary acute illness or abnormality of the extremity (skin and lymph nodes) 
targeted for vaccination. 
7. 
Eligibility for vaccination will be confirmed based on review of inclusion/exclusion criteria. 
Any subject who cannot be vaccinated due to an acute abnormality (e.g., ≥ Grade 2 acute 
illness, or abnormal vital sign deemed clinically relevant by the PI) may return once the 
acute issue has resolved, if deemed appropriate by the PI. A minimum of 48 hours must have 
passed after a documented fever (oral temperature of ≥ 38°C) before a subject can be 
vaccinated.  
8. 
The subject will be randomized if eligibility is confirmed by the PI. 
9. 
Venous blood samples (approximately 10 mL) will be obtained for immunogenicity testing. 
For participants in the CMI subset of phase 2, additional 16 mL will be collected. 
10. The randomization ID will be recorded by unblinded study staff, who will maintain a list 
documenting the study vaccine assigned and administered to given randomization IDs in a 
secure location that is not accessible to blinded study staff. The subject will be referred to by 
subject ID for the remainder of the study. The randomization ID will be required on select 
CRFs. 
11. The assigned study product will be administered. 
12. After the study product is administered, the subject will be observed by blinded study staff  
for at least 30 minutes post-injection. 
13. Vital signs and any solicited AEs will be recorded at 30 (+10) minutes post-injection. See 
Appendices 1 and 2 for relevant severity grading scales. 
14. During the observation period, the subject will be provided with a ruler, thermometer, and 
Diary Card, and given instructions on how to complete the Diary Card. The subject will be 
instructed to collect solicited AEs daily for seven days (the day of Visit 1 and the following 
six days) by recording them in the Diary Card, preferably at approximately the same time 
each day. The subject will also be instructed to record unsolicited AEs and concomitant 
medications on the Diary Card. Finally the subject will be instructed to call the PI in the 
event of any severe (Grade 3) symptoms, or any other health issues that require medical care. 
15. The subject will also be provided with a fact sheet on COVID-19 that will include contact 
details for the PI, and instructions to contact the PI in the event of COVID-19-associated 
symptoms that meet the following criteria: 

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49 
At least ONE of the following:  
• Fever (≥38°C) 
• Shortness of breath 
• Difficulty breathing 
OR 
TWO of the following for TWO or more days: 
• Chills 
• Cough 
• Fatigue 
• Muscle or body aches 
• Headache 
• New loss of smell or taste 
• Sore throat 
• Nausea or Vomiting or Diarrhea 
The fact sheet will be reviewed with the subject in clinic prior to discharge.   
16. Finally, the subject will be reminded to contact the study team to report any MAAE or SAE. 
17. The subject will be scheduled for Visit 2 (Day 8). 
18. Safety monitoring within 7 days post study vaccination will be as follows: 
• For Phase 1: The study subject will be monitored for safety on site of HMU for 24 hours 
after study vaccination. The subject will then be discharged for home and will be 
contacted on Day 4 by telephone or home visit to allow the subject to report any solicited 
or unsolicited AEs, to address any questions or concerns, and to remind the subject to 
complete the Diary Card. On Day 6, she/he will be contacted again by telephone or home 
visit for the same purpose and as a reminder to attend Visit 2 (D8). 
• For Phase 2: On the third day (48 hours) post-injection (Day 3), the subject will be 
contacted by telephone or home visit for a health check, to address any questions or 
concerns, and to remind the subject to complete the Diary Card. On Day 5, she/he will be 
contacted again by telephone or home visit for the same purpose and as a reminder to 
attend Visit 2. 
7.2.3. 
Visit 2 (Day 8) and Visit 4 (Day 36) 
At Visit 2 and Visit 4, the following procedures will be performed: 
1. 
Subject ID, addresses and telephone number(s) will be confirmed. 
2. 
Unsolicited AEs will be recorded, including assessment of relatedness to vaccination, severity, 
and outcome. Ongoing unsolicited AEs will be reviewed. 
3. 
Concomitant medications will be recorded. 
4. 
Vital signs will be measured. 
5. 
Targeted PE will be performed to assess the injection site and draining lymph nodes, and to 
evaluate any new or ongoing AE.   

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6. 
The completed Diary Card will be reviewed with the subject for completeness and accuracy. 
Possible inaccuracies will be clearly documented. Then completed pages of the Diary Card 
will be collected, and blank pages and/or additional pages will be returned to subjects for 
recording any health issue and concomitant medications until the next visit (V3/D29 and 
V7/D57 respectively). Note, the Visit 4 (Day 36) of the Phase 2 is not an onsite visit, study 
staff will call subjects to remind the Diary Card completion and bring it to study site in the 
next visit. 
 
7. 
Venous blood samples (approximately 4 mL, only in Phase 1) will be obtained for clinical 
laboratory tests (non-fasting), as follows: 
a. 
WBC count, Hgb, Plt 
b. 
Serum creatinine, ALT, AST, total bilirubin 
8. 
The COVID-19 fact sheet will be reviewed with the subject (and provided again if needed), 
including instructions to contact the PI/designee if clinical criteria for COVID-19 are met. 
9. 
The subject will be reminded to contact the study team to report any MAAE or SAE. 
10. The date of the subsequent clinic visit will be established. 
7.2.4. 
Visit 3 (Day 29) 
At Visit 3, the following procedures will be performed: 
1.  Subject ID, addresses and telephone number(s) will be confirmed. 
2. 
A urine pregnancy test will be performed for all WOCBP. 
3. 
Unsolicited AEs will be recorded, including assessment of relatedness to vaccination, 
severity, and outcome. Ongoing unsolicited AEs will be reviewed. 
4. 
Concomitant medications will be recorded. 
5. 
Vital signs will be measured prior to dosing. 
6. 
Targeted PE will be performed to evaluate any new or ongoing AE, and to confirm absence 
of exclusionary acute illness or abnormality of the extremity (skin and lymph nodes) targeted 
for vaccination. 
7. 
Eligibility for vaccination will be confirmed based on review of inclusion/exclusion criteria. 
Any subject who cannot be vaccinated due to an acute abnormality (e.g., ≥ Grade 2 acute 
illness, or abnormal vital sign deemed clinically relevant by the PI/designee) may return once 
the acute issue has resolved, if deemed appropriate by the PI/designee. A minimum of 48 
hours must have passed after a documented fever (oral temperature of ≥ 38°C) before a 
subject can be vaccinated.  
8. 
Venous blood samples (approximately 10  mL) will be obtained for immunogenicity testing 
(only in phase 1). 
9. 
The subject’s randomization ID will be recorded by unblinded study staff, who will prepare a 
dose of the assigned study product. 
10. The assigned study product will be administered. 

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11. After the study product is administered, the subject will be observed by blinded study staff 
for at least 30 minutes post-injection. 
12. Vital signs and any solicited AEs will be recorded at 30 (+10) minutes post-injection. See 
Appendices 1 and 2 for relevant severity grading scales. 
13. During the observation period, the subject will be provided with a ruler, thermometer, and 
Diary Card, and given instructions on how to complete the Diary Card. The subject will be 
instructed to collect solicited AEs daily for seven days (the day of Visit 3 and the following 
six days) by recording them in the Diary Card, preferably at approximately the same time 
each day. The subject will also be instructed to record unsolicited AEs and concomitant 
medications on the Diary Card. Finally the subject will be instructed to call the PI/designee in 
the event of any severe (Grade 3) symptoms, or any other health issues that require medical 
care. 
14. The COVID-19 fact sheet will be reviewed with the subject (and provided again if needed), 
including instructions to contact the PI/designee if clinical criteria for COVID-19 are met.  
15. The subject will be reminded to contact the study team to report any MAAE or SAE. 
16. The subject will be scheduled for Visit 4 (Day 36). 
17. Safety monitoring within 7 days post study vaccination will be as follows: 
For Phase 1: The study subject will be monitored for safety on site of HMU’s hospital for 4 
hours after study vaccination. The subject will then be discharged for home and will be 
contacted on Day 32 by telephone or home visit for a health check, to address any questions 
or concerns, and to remind the subject to complete the Diary Card. On Day 34, she/he will be 
contacted again by telephone or home visit for the same purpose and as a reminder to attend 
Visit 4 (Day 36) in Phase 1 and Visit 5 (Day 43) in phase 2. 
For Phase 2: On the third day (48 hours) post-injection (Day 31), the subject will be 
contacted by telephone or home visit for a health check, to address any questions or 
concerns, and to remind the subject to complete the Diary Card. On Day 33, she/he will be 
contacted again by telephone or home visit for the same purpose and as a reminder to attend 
Visit 5 (Day 43). 
Note: The study dates of visits after the V3/D29 visit will be adjusted according to the actual 
date of the V3/D29 visit. 
7.2.5. 
Visit 5 (Day 43) 
At Visit 5, the following procedures will be performed: 
1. 
Subject ID, addresses and telephone number(s) will be confirmed. 
2. 
Unsolicited AEs will be recorded, including assessment of relatedness to vaccination, 
severity, and outcome. Ongoing unsolicited AEs will be reviewed. 
3. 
Concomitant medications will be recorded. 
4. 
Vital signs will be measured. 
5. 
Targeted PE will be performed to evaluate any new or ongoing AE. 

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6. 
Venous blood samples (approximately 10 mL) will be obtained for immunogenicity testing. 
For participants in the CMI subset of phase 2, additional 16 mL will be collected. 
7. 
The COVID-19 fact sheet will be reviewed with the subject (and provided again if needed), 
including instructions to contact the PI/designee if clinical criteria for COVID-19 are met. 
8. 
Finally the subject will be reminded to contact the study team to report any MAAE or SAE. 
9. 
The subject will be scheduled for Visit 6 (Day 57). 
10. For Phase 2: The completed Diary Card will be reviewed with the subject for completeness 
and accuracy. Possible inaccuracies will be clearly documented. Then completed pages of the 
Diary Card will be collected, and blank pages and/or additional pages will be returned to 
subjects for recording any health issue and concomitant medications until the next visit (Visit 
6, Day 57). 
7.2.6. 
Visit 6 (Day 57) 
At Visit 6, the following procedures will be performed: 
1. 
Subject ID, addresses and telephone number(s) will be confirmed. 
2. 
Unsolicited AEs will be recorded, including assessment of relatedness to vaccination, 
severity, and outcome. Ongoing unsolicited AEs will be reviewed. 
3. 
Concomitant medications including non-study Covid-19 vaccines will be recorded. 
4. 
Vital signs will be measured. 
5. 
Targeted PE will be performed to evaluate any new or ongoing AE.   
6. 
The COVID-19 fact sheet will be reviewed with the subject (and provided again if needed), 
including instructions to contact the PI/designee if clinical criteria for COVID-19 are met. 
7. 
Finally the subject will be reminded to contact the study team to report any MAAE or SAE. 
8. 
The subject will be scheduled for Visit 7 (Day 197). 
9. 
The subject will receive a text or email every two weeks as a reminder to contact the site to 
report any MAAE or SAE. 
7.2.7. 
Visit 7 (Day 197)  
At Visit 7, the following procedures will be performed: 
1. 
Subject ID, addresses and telephone number(s) will be confirmed. 
2. 
MAAEs or SAEs that have not previously been reported will be recorded, including 
assessment of relatedness to vaccination, severity, and outcome. Ongoing MAEs and SAEs 
will be reviewed. 
3. 
Concomitant medications associated with a newly reported MAAE or SAE will be recorded, 
and ongoing concomitant medications including non-study Covid-19 vaccines reviewed. 
4. 
Vital signs will be measured. 
5. 
Targeted PE will be performed to evaluate any new or ongoing AE, and intervening MAAE 
or SAE.   

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6. 
Venous blood samples (approximately 10 mL) will be obtained for immunogenicity testing. 
For participants in the CMI subset, additional 16 mL will be collected. 
7. 
The COVID-19 fact sheet will be reviewed with the subject (and provided again if needed), 
including instructions to contact the PI/designee if clinical criteria for COVID-19 are met. 
8. 
The subject will be reminded to contact the study team to report any MAAE or SAE. 
9. 
The subject will be scheduled for Visit 8 (Day 365). 
10. The subject will receive a text or email every two weeks as a reminder to contact the site to 
report any MAAE or SAE. 
7.2.8. 
Visit 8 (Day 365, EOS) (phase 1 only) 
At Visit 8, the following procedures will be performed: 
1. 
Subject ID, addresses and telephone number(s) will be confirmed. 
2. 
MAAEs or SAEs that have not previously been reported will be recorded, including 
assessment of relatedness to vaccination, severity, and outcome. Ongoing MAEs and SAEs 
will be reviewed. 
3. 
Concomitant medications associated with a newly reported MAAE or SAE will be recorded, 
and ongoing concomitant medications including non-study Covid-19 vaccines reviewed. 
4. 
Vital signs will be measured. 
5. 
Targeted PE will be performed to evaluate any new or ongoing AE, and intervening MAAE 
or SAE.   
6. 
Venous blood samples (approximately 10 mL) will be obtained for immunogenicity testing. 
7. 
The subject will exit the study after completion of the EOS CRF. 
 
7.2.9. 
Unscheduled Contacts and Visits 
Unscheduled contacts and visits may take place at subject request or as deemed necessary by the PI or 
site staff at any time during the study. Subjects will be instructed to contact the PI/designee if clinical 
criteria for COVID-19 are met (as specified on the COVID-19 fact sheet) throughout the entire study 
period. Subjects will also be instructed to contact the site to report any MAAE or SAE throughout the 
entire study period. All unscheduled contacts and visits will be documented in the subject’s study 
records and on applicable CRFs.   
7.3. 
Subject Discontinuation 
Subject discontinuation from study procedures prior to completion of the last study visit may occur 
for any of the following reasons: 
• Withdrawal (defined as discontinuation initiated by a subject): Participation in the study is 
strictly voluntary. Subjects have the right to withdraw their consent from study participation at 
any time and for any reason, without penalty. The subject may also withdraw due to an 
adverse event. 
• 
PI-initiated: The PI/designee may, at her discretion, discontinue a subject from the study if it 

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is considered to be in the subject’s best interest to do so (e.g., for safety concerns), or if the 
subject does not comply with the study requirements. Any subject who is determined to be 
infected with SARS-CoV-2 prior to Visit 3 (Day 29) will be discontinued from the study (i.e., 
will not receive the second study injection) but will continue to be followed for safety 
assessments through Visit 8 (EOS). 
• 
Lost to follow-up: For subjects who fail to attend scheduled visits, study staff are to make at 
least three attempts to contact the subject prior to considering the subject as lost to follow-up. 
These attempts should be recorded in the source documents. 
• Sponsor-initiated: For example, if the Sponsor is obliged to end the study for administrative or 
any other reason, such as a recommendation by the DSMB based upon safety review. 
Subjects who discontinue prior to first administration of the study product will be replaced, whereas 
those withdrawn after first administration of the study product will not be replaced. 
The reason for and date of subject discontinuation will be recorded in the source documents and 
relevant CRF. Before concluding the reason for the subject’s discontinuation from the 
study, the investigator should make every effort to investigate whether an AE may have been 
related to the subject’s discontinuation from the study. For subjects considered lost to follow-up, the 
discontinuation date for the subject to be captured on the discontinuation CRF page is the date of 
the subject’s last completed study visit. 
In the event of subject discontinuation from the study, reasonable efforts should be made to conduct 
the following procedures (unless subject consent to do so has been withdrawn): 
• Update subject contact information. 
• Review the Diary Card if still in use prior to discontinuation. 
• Update any AEs that remained ongoing at the time of the subject’s last visit prior to 
discontinuation. 
• Collect any new reportable AEs and concomitant medications since the subject’s last visit, 
based on the protocol-defined reporting period at the time of discontinuation.  
• Perform a targeted PE to evaluate any newly reported AEs since the subject’s last visit.  
7.4. 
Concomitant Medications 
All concomitant medications will be recorded in source documents from Visit 1 (Day 1) through Visit 
5 (Day 57). After Visit 5, only those concomitant medications associated with MAAEs and SAEs will 
be recorded. If study subjects receive the non-study covid-19 vaccine after the Visit 5 (Day 43), then 
details of those vaccinations will be recorded. In case, subjects decide to receive non-study Covid-19 
vaccine approved by MoH, after receiving the study product (after dose 1 and dose 2) it is 
recommended to be administered 14 days after study vaccination. If they receive non-study Covid-19 
vaccine before the Visit 5 (Day 43), these subjects will not be eligible, but study team still contact 
them for safety follow-up. If study subjects receive non-study covid-19 vaccine after the Visit 5 (Day 
43), they are still in study for safety follow-up; however the blood samples collected in the Visit 8 
(Day 197) and Visit 9 (Day per365) will not be included in the Per Protocol Population, but will be 
analyzed to explore the immunogenicity interaction between study and non-study covid-19 vaccines. 
Details on concomitant medications to be recorded include the generic and/or trade name, indication, 
dosage, regimen, route of administration, and start and end dates of the medication.  

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The following concomitant medications are prohibited during the study; however, they must not be 
withheld by the treating physician if clinically indicated to treat a subject: 
• Any investigational medicinal product other than the study product  
• Administration of immunoglobulins or any blood products 
• Administration of any long-acting immune-modifying drugs (e.g., infliximab or rituximab) or 
the chronic administration (defined as more than 14 days) of immunosuppressive medications 
(includes systemic corticosteroids at doses equivalent to ≥ 0.5 mg/kg/day of prednisone; the 
use of topical steroids including inhaled and intranasal steroids is permitted). 
Use of any prohibited medication must be recorded in the CRF. Whether a subject who uses a 
prohibited medication will be included in the Per Protocol Population will be evaluated on a case-by-
case basis. 
7.5. 
Emergency Unblinding Procedure 
In the event of a medical emergency, the PI/designee may require that the blind be broken for the 
subject experiencing the emergency when knowledge of the subject’s treatment assignment may 
influence the subject’s clinical care. Every effort will be made not to unblind the subject unless it is 
considered 
absolutely necessary for the welfare of the subject. Prior to unblinding, the investigator is 
encouraged (to the extent possible, without jeopardizing the subject’s health) to contact the Sponsor 
(or designee) to discuss the decision to break the blind. 
Unblinding will occur through the secure IWRS or according to the emergency unblinding SOP, to 
which there will be 24-hour access. Documentation of the unblinding event will be captured by the 
IWRS or unblinded staff. In the unlikely event that the IWRS cannot be accessed, a backup process 
(such as contacting the unblinded pharmacist) will be provided. The PI/designee will be expected to 
provide a rationale for the necessity of unblinding, based on the expectation that knowledge of the 
subject’s treatment assignment will have a meaningful impact on the subject’s medical care in the 
short term. If a subject’s treatment assignment is unblinded, the subject will remain in the study and 
continue with protocol-defined study visits and procedures, unless there is another reason for subject 
discontinuation. The decision to unblind will be communicated to all regulatory bodies as required. 
At the end of the study, documentation of all unblinded subjects (and the rationale for unblinding) 
will be incorporated into the TMF. 
7.6. 
Management of Pregnancy 
All WOCBP will be monitored for pregnancy during the study and for the use of adequate 
contraception until completion of Visit 6 (Day 57). 
If a female subject becomes pregnant after Visit 1 (Day 1) but prior to Visit 3 (Day 29) no further 
study product will be administered. The subject will be encouraged to complete all remaining study 
visits for safety assessments alone, and if possible and agreed to by the subject, continue to be 
followed through the pregnancy outcome. The pregnancy and its outcome will be documented, even 
if birth occurs after the scheduled end of the study for the subject. The PI/designee is required to 
notify the Sponsor (or designee) within 24 hours of knowledge of a pregnancy. 
7.7. 
Clinical Procedures 

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Vital Signs 
• Temperature will be measured in degrees Celsius (recorded to the nearest 0.1 degree) by oral 
(sublingual) thermometer following at least 20 minutes of avoidance of food and drink.   
• Respiratory rate will be measured in breaths per minute. 
• Blood pressure will be measured in millimeters (mm) of mercury and heart rate in beats per 
minute by automated device or manually on the arm not used for study product 
administration. 
• Vital signs will be graded according to the toxicity grading scale in Appendix 2. 
Height and Weight 
• Height will be measured in centimeters (cm) and recorded to the nearest 0.1 cm. 
• Weight will be measured in kilograms (kg) and recorded to the nearest 0.1 kg. 
Complete Physical Examination 
• A complete physical examination will include head, eyes, ears, nose, oropharynx, neck, chest 
(auscultation), lymph nodes (neck, supraclavicular, axillary), back, abdomen (auscultation and 
palpation), musculoskeletal, skin (especially hands, arms, injection sites), and nervous system. 
Injection Site Examination 
• Erythema will be examined under standard lighting conditions and measured based on the 
maximum diameter and recorded to the nearest 0.1 cm. 
• Swelling/induration will be examined by palpation and visual inspection under standard 
lighting conditions; the examiner may temporarily mark the skin at the margins of visible 
swelling/induration, then measure at the maximum diameter and record the distance to the 
nearest 0.1 cm. 
• Local reactions will be graded according to the toxicity grading scale in Appendix 1. 
 
8. SAFETY ASSESSMENT AND REPORTING 
The PI/designee is responsible for the detection and documentation of events meeting the criteria and 
definition of an AE or SAE as provided in this protocol for the duration of the study. 
8.1. 
Collection of Safety Events 
AEs will be systematically collected at all clinic visits. Solicited AEs will be assessed in all 
subjects immediately (30 minutes) after each injection. Subjects will record solicited AEs daily in 
Diary card for the seven days following each injection, as well as record unsolicited AEs during this 
period. If a solicited AE is ongoing at a 7-day post-injection follow-up visit (Visit 2 or 4), it will be 
continued to be followed as per AE monitoring requirements. All unsolicited AEs and Solicited AEs, 
but occurs after 7 days post-injection and clinically significant safety lab tests will be recorded on the 
AE CRF. 
All AEs, including MAAEs, SAEs and AESI, will be collected through the 28-day post-second-
injection follow-up visit (Visit 6). After Visit 6, only MAAEs, SAEs, and AESI will be recorded. 
8.2. 
Definitions 
8.2.1. 
Adverse Event  

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An adverse event is any untoward, undesired, or unplanned event in the form of signs, symptoms, 
disease, or laboratory or psychological/physiologic observations occurring in a subject enrolled in the 
clinical trial. This includes all subjects from whom consent has been obtained whether or not they 
have yet been randomized and received a study product. The event does not need to be causally 
related to trial participation or receipt of a study product. An AE is temporally related to participation 
in the study and will be documented as to whether or not it is considered to be related to vaccine. An 
AE includes, but is not limited to, the following: 
• An intercurrent illness or injury during the course of the study 
• Any clinically significant worsening of a preexisting condition 
8.2.2. 
Solicited Adverse Event 
Solicited adverse events are pre-specified injection-site-specific local and systemic AEs that occur 
relatively more frequently, or are known to be associated with, immunization, and which are 
monitored actively as potential indicators of vaccine reactogenicity. Investigators will not be required 
to assess causality of solicited AEs if the onset is during the solicitation period. 
The following specific solicited AEs will be monitored for this study: 
Local solicited AEs assessed at the injection site: 
• Pain or tenderness  
• Swelling or induration  
• Erythema 
Systemic solicited AEs: 
• Fever (defined as oral temperature ≥ 38°C) 
• Headache 
• Fatigue or malaise 
• Myalgia 
• Arthralgia 
• Nausea or vomiting 
8.2.3. 
Unsolicited Adverse Event 
An unsolicited adverse event is any AE reported spontaneously by the subject, observed by the study 
staff during study visits or those identified during review of medical records or source documents. 
Solicited AEs with an onset after the seven-day solicitation period will be considered unsolicited 
AEs. In the absence of a diagnosis, abnormal physical examination findings or abnormal clinical 
safety laboratory test results that are assessed by the investigator to be clinically significant will be 
recorded as an AE. 
8.2.4. 
Medically-Attended Adverse Event 
A medically-attended adverse event is an unsolicited AE for which the subject received medical 
attention, such as during an emergency room visit or a visit to or from medical personnel (e.g., 
medical doctor).  
8.2.5. 
Adverse Event of Special Interest 

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An adverse event of special interest (AESI) is an AE 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 can be appropriate. Such an event might warrant further investigation in 
order to characterize and understand it. 
The AESI to be monitored in this study include the following: 
• Potential immune-mediated medical conditions (PIMMC), given that vaccination has been 
associated with autoimmunity (See Appendix 4)  
• AEs associated with COVID-19, given the importance to subject safety of managing any 
occurrence of COVID-19, and the possible association of vaccination with enhancement of 
COVID-19 (See Appendix 5) 
There may be additional PIMMC, AEs associated with COVID-19, or other AESI not included in 
Appendices 4 and 5 that are established by the Sponsor or regulatory authorities prior to or during 
conduct of the study. 
8.2.6. 
Protocol-Related Adverse Event 
A protocol-related adverse event is an AE that occurs from the time of enrollment until the EOS visit 
that is not considered to be related to receipt of the study vaccine, but is considered by the 
PI/designee or the Sponsor to be related to the research conditions, i.e., related to the fact that a 
subject is participating in the study. For example, a protocol-related AE may be an untoward event 
occurring during blood sampling or other protocol-specified activity. 
8.2.7. 
Treatment-Emergent Adverse Event 
A treatment-emergent AE is defined as an AE that is not present prior to administration of the study 
product, or, if present prior to the administration of the study medication, increases in intensity after 
administration of the study medication during the course of the study. 
8.2.8. 
Serious Adverse Event 
An SAE is a specific AE that: 
• Results in death. 
• Is life-threatening.* 
• Requires inpatient hospitalization or prolongation of an existing hospitalization.** 
• Results in a persistent or significant disability or incapacity.*** 
• Results in a congenital anomaly or birth defect. 
*Life-threatening refers to immediate risk of death as the event occurred per the reporter. A life-
threatening event does not include an event that, had it occurred in a more severe form, might have 
caused death but, as it actually occurred, did not create an immediate risk of death. 
For example, hepatitis that resolved without evidence of hepatic failure would not be considered life-
threatening, even though hepatitis of a more severe nature can be fatal. Similarly, an allergic reaction 
resulting in angioedema of the face would not be life-threatening, even though angioedema of the 
larynx, allergic bronchospasm, or anaphylaxis can be fatal. 
**Hospitalization is an admission to a health facility in the situation where there is an AE. A period 
of observation at a clinical trial site is not considered to represent hospitalization for the purposes of 

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SAE reporting. Hospitalization or prolongation of a hospitalization constitutes a criterion for an AE to 
be serious; however, it is not in itself considered an SAE. In absence of an AE, a hospitalization or 
prolongation of a hospitalization should not be reported as an SAE by the PI/designee on a SAE form. 
Such situations include, but are not limited to, the following: 
• A hospitalization for a preexisting condition that has not worsened. 
• Hospitalization for social reasons. 
***Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. If there is any doubt about whether the information constitutes an SAE, the information is 
treated as an SAE. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also 
usually be considered serious. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, or blood dyscrasias or convulsions that do not result in 
hospitalization. 
8.2.9. 
Severity (Intensity) of Adverse Event 
The severity of all solicited AEs will be graded from Mild (Grade 1) to Potentially Life Threatening 
(Grade 4), based on the criteria given in Appendix 1. All AEs leading to death are Grade 5 events. 
Adverse events are graded based on the worst severity grade during the illness/symptoms.  All other 
unsolicited AEs will be classified as an AE and graded based on the AE severity scale in Error! R
eference source not found. 6 below. The grading scales for solicited and unsolicited AEs have been 
derived from the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events (Version 2.1, July 2017), from the US National Institutes of Health. 
Table 6. 
Severity Grading 
Grade 
Description 
1 
Causes no or minimal interference with normal daily activities; 
intervention not indicated  
2 
Interferes with but does not prevent normal daily activities; 
intervention indicated 
3 
Prevents normal daily activities; intervention or hospitalization indicated 
4 
Causes inability to perform basic self-care activities; intervention 
indicated to prevent permanent impairment, persistent disability, or death 
8.2.10. Causal Relationship of an Adverse Event 
A suspected adverse drug reaction (ADR) means any AE for which there is a reasonable possibility 
that the study vaccine caused the AE. A reasonable possibility means there is evidence to suggest a 
causal relationship between the vaccine and the AE. All cases judged by either the PI/designee or 
the Sponsor as having a reasonable suspected causal relationship to the study vaccine will qualify 
as ADRs. Medical judgment will be used to determine the relationship, considering all relevant 

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factors, including pattern of reaction, temporal relationship, confounding factors such as 
concomitant medication, concomitant diseases, and relevant history.  
The likelihood of the relationship of the AE to study vaccine is to be recorded as follows: 
• Related: There is a reasonable causal relationship between the vaccine administered and the 
AE. 
• Not Related: There is no reasonable causal relationship between the vaccine administered 
and the AE. 
Note: solicited reactogenicity events will not be judged for relatedness. 
8.2.11. Assessment of Outcome of Adverse Event 
The outcome of the AE will be assessed and recorded as per the following categories: 
• Ongoing. 
• Recovered/resolved. 
• Recovered/resolved with sequelae. 
• Fatal. 
• Unknown. 
8.3. 
Adverse Event Recording and Reporting 
Recording and reporting of all AEs will occur from signing of the ICF (enrollment) through 28 days 
post-second injection (Visit 6) for each study subject receiving study product. SAEs, MAAEs, and 
AESI will be recorded throughout the study period. The Study staff must completely and promptly 
record each AE in the source documentation and on the AE CRF, regardless of relationship to the 
vaccine administered/procedure as determined by the PI/designee. The PI/designee will attempt, if 
possible, to establish a diagnosis based on the signs and symptoms. When a diagnosis for the reported 
signs or symptoms is known, the PI/designee will report the diagnosis as the AE, not the signs and 
symptoms. Adverse events will be classified by MedDRA term and by severity/intensity, relatedness, 
and outcome. 
Enrolled subjects who subsequently screen fail (i.e., who never underwent randomization) or 
withdraw consent will have any AEs recorded from enrollment until the time they are determined to 
be ineligible for randomization or withdraw consent. These AEs will be listed in separate appendices 
from those subjects randomized and vaccinated. For the purposes of data capture they will be closed 
at the point the subject is deemed ineligible. 
Reporting of AEs will follow the regulatory guidelines of the Ministry of Healthand NIHE’s EC in 
regard to requirements, processes and forms. 
8.4. 
Serious Adverse Event Reporting 
If an AE is classified as serious, an SAE form will be completed and submitted within 24 hours of the 
PI/designee becoming aware of the SAE, including information on the location, severity, relatedness, 
and clinical summary of the event to the Sponsor to initiate any PSRT evaluation and any additional 
reporting requirements. In addition, the SAE submission will follow the regulatory guidelines of the 
Ministry of Health and NIHE’s IRB in regards to requirements, processes and forms. It is the 
responsibility of the Sponsor to ensure that Dynavax Technologies Corporation (manufacturer of the 

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adjuvant CpG 1018) and the other Consortium manufacturers are notified of SAEs and other notable 
safety events per agreed procedures and timelines. Any SAE deemed related to study vaccine that is 
ongoing at the time of last subject last visit (LSLV) will continue to be followed until it is resolved, 
assessed to be resolved with sequelae, or assessed to be stable/chronic. SAEs deemed not related to 
study vaccine that are unresolved at the time of LSLV will be classified as ongoing. 
8.5. 
Unanticipated Problems 
All unanticipated problems will be reported in the continuing review report submitted to the Ministry 
of Healthand NIHE’s IRB per reporting requirements of each regulatory body. All serious 
unanticipated problems involving risk to participants or others will be promptly (within 48 hours) 
reported by telephone, by email, or by facsimile to the Sponsor. Follow-up reports will be submitted 
as soon as additional information becomes available. 
 
9. SAFETY MONITORING 
The PI/designee will be responsible for continuous monitoring of all study subjects’ safety. In case of 
urgent need, subjects will have the means to get in contact with study staff at any time (24 hours per 
day). The PI/designee will also be available by cell phone 24-hours per day for medical emergencies. 
9.1. 
Protocol Safety Review Team 
Safety will be monitored routinely throughout the study by the PSRT, which includes the PI/designee 
and other site investigators, the IVAC Clinical Lead, and the Medical Monitor. The PSRT will be 
continuously involved in safety monitoring and be available to address any urgent medical queries or 
safety concerns related to any subject’s participation in the study. Data management personnel will 
ensure that the PSRT receives immediate notification of all reported SAEs and any other predefined 
AEs (e.g., Grade 3 AEs). The PSRT will convene to review blinded safety data on a weekly basis until 
D43 of the last subject in each phase, then at least once monthly until the end of the study.  
During meetings the PSRT will review blinded safety reports and review any outstanding medical or 
safety queries from the previous review. The blinded safety reports will contain at a minimum, 
subject disposition and discontinuations, all new Grade 3 and persistent (beyond 6 days post-IP 
administration) solicited AEs, and all new unsolicited AEs. Cumulative safety data reports will also 
be made available continuously for review by PSRT members. In addition, the PSRT will review all 
major protocol deviations in an expedited manner and all other protocol deviations at least on a 
monthly basis to assess for any potential safety implications, and will provide guidance in the 
preparation of corrective action plans. The PSRT may also discuss any other study conduct issues that 
impact study integrity and subject safety, including but not limited to data quality and critical 
monitoring findings. The PSRT may refer any safety concerns to the DSMB. The full responsibilities 
and procedures of the PSRT will be detailed in the Safety Management Plan. 
9.2. 
Data and Safety Monitoring Board 
A DSMB, composed of at least three independent members with expertise in vaccine clinical trials, 
will be convened to provide additional safety oversight. In Phase 1, the DSMB will meet to review 
unblinded safety data through Day 57 (V6), and on the basis of this review provide a recommendation 
for advancing to Phase 2 (i.e. the DSMB will indicate whether advancement to Phase 2 is warranted 
based on the reviewed safety data, and whether specific COVIVAC formulations should not be 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
62 
considered for advancement due to safety concerns). In the Phase 2 segment, the DSMB will again 
meet to review unblinded safety data through Day 57 (V6), and on the basis of this review provide a 
recommendation for advancing to Phase 3 (i.e. the DSMB will indicate whether there are any safety 
concerns with one or the other selected COVIVAC formulation evaluated in Phase 2).  
The DSMB will also meet if a study pause rule is met, or the PSRT elects to implement a study 
pause. If this occurs, no further enrollment will occur, and no study product will be administered until 
the DSMB approves lifting the pause based on unblinded review of all safety data accrued during the 
trial. If the study is permanently terminated, subjects who have already received study product will 
continue with all scheduled protocol visits and assessments; however, they will not receive any 
further study product.  
DSMB reviews will indicate whether or not safety concerns were identified, and whether the trial 
should continue without change, be modified, or be terminated. The Sponsor will carefully consider 
the DSMB recommendations. If the Sponsor does not agree with these recommendations, a meeting 
will be held between the Sponsor, PI, and DSMB to reach consensus on the appropriate action(s) to 
take in regard to the trial. However, if attempts to reach consensus fail, the Sponsor’s opinion will 
prevail. In such situations, the Sponsor will inform the MoHand NIHE’s EC of the Sponsor’s 
perspective, and any changes to the trial. The PSRT, PI or IVAC Clinical Lead may also seek 
additional guidance from the DSMB as dictated by the occurrence of certain events that do not 
warrant a study pause.  
The composition, responsibilities and procedures of the DSMB will be detailed in the DSMB Charter. 
 
 
9.3. 
Pause Rules 
The DSMB will be convened if it is established that any of the following study pause rules has been 
met during the conduct of the trial:   
• Rule 1: Occurrence of any SAE attributed to study vaccine in  ≥ 1 subject  
• Rule 2: Occurrence of the following Grade 3 or greater injection site solicited AE in ≥ 1 
subject: ulceration, necrosis, or sterile abscess at the injection site requiring drainage or 
surgical intervention. 
• Rule 3: Occurrence of the same Grade 3 solicited AE, unsolicited AE attributed to study 
vaccine, or laboratory abnormality in ≥ 10.0% of unique subjects. In the case of fever, pain 
and tenderness, the episode must last longer than 24 hours, and, in the case of fever, be 
confirmed by the PI/designee without evidence of other medical causes. Note: for the first 
20 randomized subjects, this pause rule will only be met if the grade 3 AE or laboratory 
abnormality occurs in ≥ 2 unique subjects. 
9.4. 
Protocol Deviation  
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, site SOP 
requirements, or departure from applicable regulatory requirements. The noncompliance may be 
either on the part of the subject or the site team/PI. 

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63 
Major protocol deviations are a subset of protocol deviations that may significantly impact the 
completeness, accuracy, and/or reliability of the study data or that may significantly affect a subject's 
rights, safety, or well-being. Examples of major protocol deviations may include: failure to obtain 
informed consent, failure to reAport SAEs, enrolling subjects in violation of key eligibility criteria 
designed to ensure a specific subject population, or failing to collect data necessary to interpret 
primary endpoints, as this may compromise the scientific value of the trial.. 
When appropriate, corrective actions and preventive actions (CAPAs) will be developed by the site to 
address deviations, and will be implemented promptly. These practices will be consistent with ICH 
E6 Guidelines. 
 
10. STATISTICAL CONSIDERATIONS 
10.1. Overview and General Considerations 
This is a randomized, placebo-controlled, observer-blind, Phase 1/2 trial in healthy male and non-
pregnant female subjects of age ≥18 and ≥ 60years old, inclusive. A maximum of 120 eligible 
subjects will be accrued in Phase 1, and a maximum of 375 eligible subjects will be accrued in Phase 
2. 
The first phase is a first-in-human study in 120 healthy subjects of age 18-59 years old designed to 
evaluate the COVIVAC vaccine at three different dose levels (1 µg, 3 µg, 10 µg) without adjuvant 
and one dose level (1 µg ) with the adjuvant CpG 1018. Randomization into each group will be age 
stratified with half of subjects between 18-39 years of age and the other half 40-59 years of age.  
 
In the second phase of this combined Phase 1/2 study, 300 adults  ≥18 and ≥ 60years old will be 
randomized (1:1:1) to AstraZeneca, or one of two selected formulations of COVIVAC 3 µg 
(evaluated in Phase 1) and 6 µg (an intermediate dose level) based on Phase 1 safety and 
immunogenicity. To ensure that adequate safety and immune data will be available from older and 
elderly adults to inform the selection of COVIVAC formulation to advance to Phase 3 studies, 
randomization will be age stratified by group with approximately one third of subjects in 18-39, 40-
59, and ->60 years of age. 
 
10.2. Randomization Procedures 
Randomization for Phase 1 will be conducted after accumulation of 120 eligible subjects. 
Randomization will be stratified by gender and age (less than 40 years old and 40 to 59 years old, 
with approximately 50% of subjects in each age stratum). This is to ensure the groups are as similar 
(homogenous) as possible to ensure the down-selection of formulations is not biased by differences in 
demographic characteristics of the groups (such as age and gender). Randomization details will be 
outlined in a Randomization Plan prior to study initiation. 
Each group will be divided into two subgroups, a sentinel subgroup (n=6) and a larger subgroup 
(n=24) that includes the remaining subjects to be evaluated at that dose level (or for that formulation 
in the case of the one adjuvanted treatment group). Initially, a sentinel subgroup of 6 subjects will be 
randomized to receive COVIVAC 1 µg or placebo in a 5:1 ratio. Sentinel subjects will be monitored 
for reactogenicity and safety through Day 8 (Visit 2), including for the initial 24 hours post-injection 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
64 
in clinic. If the PSRT has no safety concerns based on blinded review of all safety data, including 
clinical laboratory results, through Visit 2, the second subgroup of 24 subjects will be randomized to 
receive COVIVAC 1 µg or placebo at the same ratio; on the same day, the sentinel subgroup  (n=6) 
for the second dose level to be evaluated (COVIVAC 3 µg) can be randomized to receive study 
vaccine or placebo in a 5:1 ratio, and so on for the subsequent dose level and formulation (see Table 
4).  The same procedure will be used for the COVIVAC 10 µg and COVIVAC 1 µg + CpG arms for a 
total of n=25 in each active group and n=20 in the placebo group. Randomization will be stratified by 
age (less than 40 years old and 40 to 59 years old) with approximately 50% of subjects in each 
stratum. 
After the interim analysis of data from the first phase informs the down selection to two candidate 
groups 375 adults  ≥18 and ≥ 60years old will be randomized (1:1:1) to AstraZeneca, or one of two 
selected formulations of COVIVAC 3 µg (evaluated in Phase 1) and 6 µg (an intermediate dose level) 
based on Phase 1 safety and immunogenicity. Twelve (12) subjects in each of the three Phase 2 
groups (equally distributed between the three age strata) will be selected for CMI at the time of 
randomization. Randomization will be age stratified by group with approximately one third of 
subjects in 18-39, 40-59, and ≥60years of age. 
10.3. Sample Size and Power 
This Phase 1/2 study has a two-part selection design with group elimination after the first part (i.e. 
Phase 1). A total of 25 (n1) subjects per group will be randomized across 4 candidate and one placebo 
group (n1=20) in the first phase. Assay titers will be analyzed on the log scale. The sample size and 
power calculations assume an interim analysis will be conducted after D43 of the first phase to 
eliminate two candidate groups by selecting the two groups with the largest means. Additionally, the 
observed seroresponse rate (defined as the percentage of subjects in a treatment group with at least a 
4-fold rise from baseline in 80% neutralizing antibody titers) will need to be at least 52% at the lower 
limit of the 95% exact confidence interval. Based on this criterion, there is less than 10% chance of 
incorrectly failing to consider advancing a vaccine candidate with a true seroresponse rate of 85% or 
higher, which is estimated to be the minimum response rate that would be consistent with further 
investment in an additional second-wave COVID-19 vaccine. The Sponsor may consider other factors 
in selecting the two most suitable candidates to advance to second phase. In the second phase, 125 
and 50 (n2) additional subjects will be randomized to the two candidate groups and the placebo group, 
respectively. The final analysis will be conducted on the full samples from the first and second phase 
(n1 + n2). 
Safety: Assuming 25 evaluable subjects per group in the first phase (and for elderly subjects enrolled 
in the second phase) and 150 total subjects (n1 + n2) in the two candidate groups included in the 
second phase, the probability of observing at least one serious or severe adverse event by the 
underlying rate is shown in Table 7. If no events are observed the upper bound of the exact 95% 
confidence interval would be 13.7% for the three eliminated groups and 2.4% in the two selected 
groups. 
Table 7. Probability to observe at least one serious or severe adverse event by sample size and 
underlying event rate. 
Sample size per 
group 
True Event Rate 
Probability to 
observe at least one 

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65 
25  
10.0%  
92.8%  
25  
7.5%  
85.8%  
25  
5.0%  
72.3%  
25  
2.5%  
46.9%  
150  
10.0%  
99.9%  
150  
7.5%  
99.9%  
150  
5.0%  
99.9%  
150  
2.5%  
97.8%  
150  
1.0%  
77.9%  
150  
0.5%  
52.9%  
 
Immunogenicity: Groups with seroresponse below 52% at the lower limit of the 95% exact 
confidence interval will not be considered for selection for the second phase. This provides 90% 
power to correctly advance candidates with a true seroresponse rate ≥85%. 
This is a two-stage selection design for selecting the group with the largest mean. Power for selecting 
the candidate with the largest true mean is driven both by the variability and the smallest difference 
between the highest mean and the means in the other three candidate groups.  
Table 8 shows the power to correctly select the candidate with the largest true mean in the first phase 
(to advance to the second phase) and the overall power for the Phase 1/2 by minimum fold-difference 
(on the titer scale) between the highest mean and the other means, assuming log10 variability of 0.5. 
These calculations assume in the first phase there are n1=22 evaluable subjects in the four candidate 
groups, two groups are eliminated after the first phase, there are n2=112 additional evaluable subjects 
in the remaining two candidate groups at D43 of second phase (n1 + n2=134), and µ4> µ1= µ2= µ3. 
Table 8. Power to select the candidate with the highest true mean to progress to second phase 
and overall for the Phase 1/2 overall by minimum fold-difference between the highest candidate 
mean and the other means, assuming log10 variability of 0.5. 
Fold-difference Phase 1 down-
selection power 
Power for overall 
Phase 1/2 
1.1  
62%   
46%   
1.2  
73%   
66%   
1.3  
82%   
78%   
1.4  
87%   
86%   
1.5  
91%   
91%   
1.6  
94%   
94%   

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
66 
1.7  
96%   
96%   
1.8  
98%   
98%   
1.9  
99%   
99%   
2.0  
99%   
99%   
 
10.4. Definitions of Populations to be Analyzed 
10.4.1. Enrolled Population 
All subjects who provide written informed consent, regardless of the subject’s screening, 
randomization, and treatment status in the study. 
10.4.2. Exposed Population 
All subjects in the enrolled population who were randomized and received at least one vaccination 
dose (i.e., were accrued). 
10.4.3. Safety Analysis Population 
All subjects in the exposed population for whom any safety data is available.  All safety analyses will 
be performed using this population.  The denominators for different safety endpoints may vary 
according to the number of subjects with available data for the specific endpoint. For instance, the 
solicited local and systemic adverse event endpoint will be based only on those who have the 
corresponding CRF data regardless of other safety data. Treatment groups for safety analysis will be 
assigned according to the actual treatment received. 
10.4.4. Full Analysis Population 
All subjects in the exposed population for whom any post-study product administration 
immunogenicity results are available. An immunogenicity analysis will also be performed using this 
population. 
10.4.5. Per Protocol Population 
All subjects in the exposed population who have no major protocol deviations that are determined to 
potentially interfere with the immunogenicity assessment of the study product. 
This population will serve as the primary analysis population for the immunogenicity endpoints. The 
population will be adapted by time point to include all eligible subjects’ data up to the time of 
disqualifying protocol deviation. The criteria (e.g., intake of prohibited medication expected to 
influence the immune response) for exclusion of subjects from the per protocol population, and 
determination of any exclusions based on a blinded review of the data, will be established before 
database freeze and lock for both interim and final analyses, respectively. 
 
10.5. Analysis Sequence and Analytical Methodology 

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67 
Interim analyses will be performed after the last subject in the first phase has completed Visit 6 (Day 
57) assessments and all the results are available. At the time of the interim analysis safety results  
(unblinded to the DSMB only) and immunogenicity results (unblinded at group level only) will aid in 
the selection of formulations to evaluate in the second phase of the study. Appendix 6 is a template of 
the interim study report that will be generated based on this analysis. 
A second interim analysis will be performed after the last subject has completed Visit 6 (Day 57) 
assessments and all the results are available.  The second interim analysis of immunogenicity and 
safety endpoints will aid in the selection of a formulation to be evaluated in a future Phase 3 trial. 
A final analysis on all safety and immunogenicity data will be performed after the study ends, when 
all additional safety and immunogenicity data have been collected following the last subject’s last 
study visit (Visit 8, Day 365), and the database is cleaned and locked. Detailed statistical procedures, 
listings, table shells, and figures will be provided in a separate statistical analysis plan (SAP) which 
will be finalized prior to the interim analyses. 
Unless otherwise specified, all statistical test will be two-sided with a significance level of 0.05. A 
95% CI will be provided for estimates, as appropriate. All statistical analyses will be performed using 
SAS® software version 9.4 or later.  
10.5.1. Analysis of Demographic and Baseline Characteristics 
Baseline demographics and characteristics, including age, height, weight, sex, race ethnicity, and 
BMI will be summarized for both the exposed and per protocol populations by treatment group using 
descriptive statistics (mean, standard deviation, median, 25th and 75th quartiles, minimum and 
maximum for continuous and rates for categorical). 
For the exposed population, medical history will be listed and summarized by category. Using the 
WHO Drug Dictionary, concomitant medications will be tabulated by anatomical therapeutic 
chemical (ATC) classification, preferred drug name and treatment group. Medical history will be 
tabulated by MedDRA System Organ Class (SOC), Preferred Term (PT) and treatment group. 
Summaries of subject disposition will be prepared for all subjects, including the number and percent 
enrolled, screened, randomized, and administered study product, as well as a CONSORT diagram 
describing study participation and discontinuation. The reasons for screen failures and 
discontinuations will be summarized and listed. 
A summary and listing of visit attendance will be prepared, in addition to a summary and listing of 
study product administration and sample collection/availability for each sample. 
10.5.2. Analysis of Primary Safety Objectives 
All safety assessment will take place in the safety analysis population, according to the treatment 
received.  All subject-level percentages (solicited/unsolicited AEs, clinical safety laboratory 
abnormalities, etc.) will be supplemented with two-sided 95% CIs computed via the Clopper-Pearson 
method.  Individual summaries (denominators for percentages) will be limited to the number of 
subjects with the appropriate analysis population with the data available for analysis for the given 
endpoint. Summaries will be provided overall by group and by stage and age strata. 
Solicited local and systemic adverse events: All solicited AEs will be summarized according to 
defined severity grading scales. Frequencies and percentages of subjects experiencing each solicited 
AE will be presented for each symptom severity. Summary tables showing the occurrence of any 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
68 
local or systemic solicited AE during the first 7 days after each administration of study product. 
Data listings of all solicited AEs will be provided by subject. For common AEs group comparisons 
may be explored. 
Clinically significant hematological and biochemical measurements: For clinical safety laboratory 
data collected at screening and 7 days post-first administration of study product (Visit 2, Day 8) and 
post-second administration of study product (Visit 4, Day 36), individual Hgb, WBC count, Plt, AST, 
ALT, total bilirubin, and creatinine values will be presented as number of subjects out of range 
(above and below normal range as appropriate) and tabulated by toxicity grading, relatedness, and 
study group. In addition, changes from baseline (median/interquartile range) will be presented. 
Unsolicited AEs: All unsolicited AEs with onset occurring during the first 28 days following study 
product administration will be assessed for severity and as either related or not related to study 
product by the investigator. 
MAAEs and SAEs: All MAAEs and SAEs through Visit 8 (Day 365) will be recorded and the 
number, severity, and relatedness to study product will be summarized. Subject-wise data listing will 
be provided. 
When an AE occurs more than once for a subject, the subject will be only counted once for the 
corresponding PT according to the maximum severity of the events. A summary table will be 
prepared for unsolicited AEs comprised of the following categories: 
• Unsolicited AEs 
• Related unsolicited AEs 
• MAAEs 
• Related MAAEs 
• SAEs 
• Related SAEs 
• SAEs leading to death 
• Unsolicited AEs leading to subject discontinuation 
Adverse events of special interest: The number, severity, and relatedness of adverse events of special 
interest (AESI), including  
• PIMMC 
• AEs specific to COVID-19 
will be summarized and provided in subject-wise data listings. 
10.5.3. Analysis of Immunogenicity objectives (Secondary Objectives for the Phase 1, 
Primary Objective for the Phase 2) 
The analysis of immunogenicity will be performed on the per protocol population as the primary 
analysis and the full analysis population as a secondary analysis. Analyses described below will be 
summarized in the interim analyses for all subjects included in the first phase of the study.  In the 
second interim and final analyses, the candidates that advanced to the second phase will be 
summarized by phase, age group (18-59 years and ≥60years), and overall. Relative endpoints derived 
from GMFR will include all subjects from the per protocol population. Absolute endpoints such as 
those derived from the GMT will exclude baseline seropositive subjects. 

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69 
Immunogenicity data will be descriptively analyzed. For estimation of the GMT, GMT ratio, and 
corresponding confidence limits, analyses will incorporate censoring where appropriate and log-
scale coefficients will be back-transformed in order to compute the estimate and corresponding 
confidence limits for the relevant quantity. GMFRs will be computed using age-adjusted estimates of 
the log difference of the paired samples, with corresponding CIs computed via the t-distribution, 
utilizing the antilog transformation to present the ratio. Analyses of binary variables will include 
95% CIs computed via the Clopper-Pearson method. Additionally, the distribution of the titers will 
be summarized using reverse cumulative distribution curves. 
NAb titers against SARS-CoV-2 pseudovirus will be measured by pseudovirus-based neutralization 
assay and summarized at baseline, 28 days after the first vaccination, and 14 days, 6 months and 12 
months after the second study injection overall and by age group (18-59 years and ≥60years) with: 
• GMT with 95% CIs (including baseline), 
• GMFR from baseline with 95% CI, and 
• Percentage of subjects with NT50 and NT80 (phase 1 only) seroresponses against 
SARS-CoV-2 pseudovirus at 28 days after the first vaccination, and 14 days, 6 months 
and 12 months after the second vaccination as defined by  
o a ≥ 4-fold increase from baseline, and  
o a ≥ 10-fold increase from baseline. 
Anti-S IgG antibody titers will be measured by ELISA and summarized at baseline, 28 days after the 
first vaccination, and 14 days, 6 months and 12 months after the second study injection overall and by 
age group (18-59 years and ≥60years) with: 
• GMTs with 95% CIs (including baseline), 
• GMFR from baseline with 95% CI, and 
• Percent of subjects with IgG seroresponses and 95% CI of 
o ≥ 4-fold increase from baseline 
o ≥ 10-fold increase from baseline 
10.5.4. Analysis of Exploratory Objectives 
The S protein-specific T cell response elicited by each of two selected COVIVAC formulations will 
be measured via ELISpot assay at baseline, 14 days, and 6 months after the second vaccination in a 
subset of subjects enrolled in the second phase of the study. The magnitude, phenotype, and cytokine-
expressions pattern of S protein-specific T cells will be descriptively analyzed by timepoint (absolute 
and relative to baseline) by study arm. The anti-NDV HN IgG immune response elicited by each 
formulation of COVIVAC will be measured by ELISA, at baseline, 28 days after the first 
vaccination, and 14 days and 12 months after the second vaccination, in subjects enrolled in the 
second phase of the study, and be summarized with GMTs with 95% CIs.  
Other exploratory assays to characterize the immune response to COVIVAC may also be performed. 
Details of all exploratory analyses will be described in the SAP. 
10.6. Multiplicity 
As the two-stage selection design relies on ranking of GMTs, not testing of differences between 
candidate groups, no adjustment for multiplicity will be performed. 

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70 
10.7. Handling of Subject Discontinuations and Missing Data 
Missing immunogenicity data will not be imputed and will be analyzed as if they were randomly 
missing. Over the study period, the frequency and percentage of subjects who discontinue from the 
study will be provided by treatment group. All subjects who discontinue post-randomization will be 
further described regarding their time to and their reasons for discontinuation. For subjects who 
discontinue from the study, their data collected before discontinuation will be analyzed under the 
analysis populations as applicable. 
 
11. LABORATORY EVALUATIONS 
11.1. Blood Sample Collection, Distribution, and Storage 
Venous blood samples obtained for clinical laboratory tests will be processed and labeled at the site, 
and sent to the lab of HMU’s hospital (phase 1), blood sample for screening HBV and HCV test will 
be processed and labeled at the site, and sent to the lab of National Institute of Hematology and Blood 
Transfusion. Blood samples obtained to evaluate secondary immunogenicity objectives will be 
processed, and serum samples aliquoted, labeled, and stored at -70°C in freezers, as per instructions 
provided in the Laboratory Manual, before being tested at Nexelis (Quebec, Canada). All stored 
serum samples will be logged into a secure database.  
The volume of blood required for the different categories of assays at different visits are 
shown in Table 9.  
 
Table 9.   
Blood Volume Requirements 
Lab Panels 
Tests 
Screen 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Hematologya:  
WBC, hgb, plts 
2.5 mL 
- 
2.5 mL 
- 
2.5 mL 
- 
- 
- 
Viral Serologya:  
HBsAg, HCV Ab 
2 mL 
- 
- 
- 
- 
- 
- 
- 
Chemistrya: 
creatinine, AST,  
ALT, t bili 
1.5 mL 
- 
1.5 mL 
- 
1.5 mL 
- 
- 
- 
Humoral 
Immunity: 
PNA, ELISAs 
- 
10 mL 
- 
10 mLb 
- 
10 mL 
- 
10 mL 
CMI:* 
ELISpot 
- 
16 mL 
- 
- 
- 
16 mL 
- 
16 mL 
 
Total  Volume 
(+ CMI) 
 
 
6 mL 
 
10 mL 
(26 mL) 
 
4 mL 
 
10 mL 
 
4 mL 
 
10 mL 
(26 mL) 
- 
 
10 mL 
(26 mL) 
a Only in Phase 1 
b Only in phase 1 
* Subset of subjects in Phase 2 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
71 
 
 
11.2. Safety Clinical Laboratory Assays 
Protocol-mandated screening and clinical safety laboratory tests will be performed at the clinical 
laboratory of HMU’s hospital (phase 1), screening HBV and HCV test will be performed at the site, 
and sent to the lab of National Institute of Hematology and Blood Transfusion (phase 2), which are 
certified with International Organization for Standardization (ISO) 15189.  
If clinically significant abnormalities are identified during screening, subjects will be referred for 
further medical management. If identified during the study, subjects may be asked to return to the 
study clinic for further evaluation, including clinical evaluation and repeat laboratory testing as 
warranted. 
11.3. Immunological Assays (Secondary Objectives) 
Assays to evaluate secondary immunogenicity objectives will be performed at Nexelis, as follows: 
SARS-CoV-2 pseudovirus neutralization assay (PNA) 
The PNA will be used to quantify the functional humoral immune response against SARS-CoV-2 by 
measuring the 50% and 80% neutralizing titer (NT50 and NT80) against a SARS-CoV-2 pseudovirus. 
The pseudotyped virus particles are made using a genetically modified Vesicular Stomatitis Virus that 
expresses the wild-type spike protein of SARS-CoV-2 (Wuhan strain) and contains a luciferase reporter 
which can be quantified in relative luminescence units (RLU).  NT50 and NT80 are determined based on 
the dilution of serum required to achieve 50% and 80% reduction in RLU value compared to 
pseudoparticle control. The assay has been qualified. 
SARS-CoV-2 pre-fusion Spike IgG ELISA 
The ELISA assay detects IgG antibodies to the full-length pre-fusion spike protein of SARS-CoV-2. 
Serum antibody content is expressed in ELISA Units (ELU)/ml.  The assay has been validated. 
At the completion of all the testing, the samples will be either destroyed or stored at an appropriate 
place in a designated freezer at Nexelis or at a Sponsor-designated facility. The Sponsor will be 
responsible for the oversight of sample storage and destruction.  
11.4. Microbiological Assays 
Nasal/pharyngeal swabs will be collected from subjects who experience signs and/or symptoms of 
COVID-19 that are of sufficient severity to warrant testing for SARS-CoV-2 infection. The testing 
will be performed at the Laboratory of virus transmitted from animal to human, Virus Lab 
Department of NIHE, a CLIA-certified diagnostics laboratory, using a singleplex RT-PCR assay. In 
addition to detecting presence of virus, the assay also provides the PCR cycle threshold (Ct) value, 
which may be used as an estimate of viral load. When swabs are received at the laboratory, they will 
be processed and then divided into two aliquots. The first aliquot will be used to test for presence of 
SARS-CoV-2, with results available on the day the swab was received. The second aliquot will be 
stored in a designated freezer for possible additional testing, including for other respiratory viral 
pathogens if judged to be helpful in the clinical management of individual cases.  
11.5. Assay Qualification, Standardization, and Validation 

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72 
Assays employed to evaluate the primary safety laboratory endpoint have been properly validated and 
will be run with adequate controls. Immunological assays have been validated, or qualified, and are 
run with adequate controls. 
11.6. Biohazard Containment 
As transmission of blood-borne pathogens can occur through contact with contaminated needles, 
blood, and blood products, appropriate blood and secretion precautions will be employed by all 
personnel in the drawing of blood and handling and shipping of all specimens for this study, as 
recommended by the US Centers for Disease Control and Prevention. All dangerous goods materials, 
including diagnostic specimens and infectious substances, must be transported according to 
instructions detailed in the International Air Transport Association (IATA) Dangerous Goods  
Regulations. Biohazardous waste will be contained according to institutional, transportation/carrier, 
and all other applicable regulations. 
 
12. DATA MANAGEMENT 
The Sponsor-designated CRO’s study monitors will visit the site at regular intervals, as per the 
Monitoring Plan, and perform pre-agreed source data verification of the data recorded in the 
electronic data capture (EDC) system against the source documents available at the site. In addition, 
missing data forms and fields will be queried by daily electronic edit checks or through manual edit 
checks of the data by the data management team. Study monitors will closely evaluate pre-screening 
data, inclusion/exclusion criteria, informed consents, data entry timeliness, and visit dates and 
windows to ensure integrity of the study is maintained. 
Any data discrepancies generated by the system will be flagged in the EDC system for the site staff 
to provide a satisfactory resolution within the EDC system. The data management team will review 
all the data discrepancy responses by the site to ensure the correctness of data. The medical history 
events and the AEs will be coded using MedDRA dictionary version 21.1 or later and the 
concomitant medications will be coded using the WHO Drug Dictionary. After completion of data 
coding and resolution of all the queries in the database, the database will be declared to be complete 
and accurate and will be locked for final statistical analysis of primary and secondary endpoints. 
12.1. Case Report Form Development and Completion 
Based on the final protocol of the study, a comprehensive set of CRFs will be prepared to capture all 
the relevant data required for analysis and reporting. This study will utilize an EDC system such that 
the entire study data can be maintained in a secure electronic system. No written or electronic data 
recorded prior to the study will be included in the CRFs or EDC system respectively. 
All study data will be collected by the clinical study staff using designated source documents and will 
be entered in the EDC system in an anonymized form. The study database will identify study subjects 
only by unique study identification numbers through screening (subject ID) and randomization 
assignments (randomization ID) and will not contain any identifying information such as name, 
address or personal contact information, or any other regional/state/national identification number. 
CRFs will be reviewed by the clinical team who are responsible for ensuring that they are accurate 
and complete.  
The data management activities will be performed as per the CRO’s SOPs. The appropriately trained 
site personnel will ensure that the study data recorded in the EDC system is verifiable with the source 

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73 
documents available at the site. To ensure that data are entered in a timely fashion so as to monitor 
safety of the study, it is expected that the site will maintain data entry with a minimal expectation of 
three business days from subject clinic visit. The study monitor plan will include assessments of data 
entry timeliness.  
The study site will maintain the source documents for each study subject. The source documents and 
other supporting documents will be kept in a secure location. Source documentation will be available 
for review by the study monitor to ensure that the collected data are consistent with the CRFs. 
12.2. Record Archival 
12.2.1. Archiving Data at Study Site 
The study site will maintain appropriate medical and research records for this trial, in compliance 
with ICH GCP, regulatory, sponsoring organization and institutional requirements for the protection 
of confidentiality of subjects. The site will permit authorized representatives of the Sponsor and 
regulatory agencies to examine (and when required by applicable law, to copy) clinical records for the 
purposes of quality assurance reviews, audits, and evaluation of the study safety and progress. After 
completion of data coding and resolution of all the queries in the database, the database will be 
declared to be complete and accurate and will be locked for final statistical analysis and made 
available to the Sponsor for long-term storage in a master file. 
12.2.2. Data Storage and Archival 
The study monitor will provide the PI with an Investigator Site File, which will be used to file the 
investigator’s brochure (IB), protocol, drug accountability records, correspondence with the EC, 
Sponsor, CRO, and other study-related documents. The PI/designee will maintain, and store 
securely, complete, accurate and current study records throughout the study. 
As required by ICH GCP guidelines, the PI will keep essential documents until at least two years 
after the last approval of a marketing application in an ICH region, and until there are no pending or 
contemplated marketing applications in an ICH region, or at least two years have elapsed since the 
formal discontinuation of clinical development of the study product. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. The documents will be archived either at Clinical Trial Center at NIHE 
or at any other secure location as agreed upon with the Sponsor. It is the responsibility of the Sponsor 
to inform the PI/institution as to when these documents no longer need to be retained. Subjects’ 
medical records and other original data will be archived in accordance with the local regulations or 
facilities of the investigational site. 
12.3. Posting of Information on Clinicaltrials.gov 
Study information from this protocol will be posted on Clinicaltrials.gov. 
12.4. Confidentiality 
Documented evidence that the PI is aware and agrees to the confidential nature of the information 
related to the study must be obtained by means of a confidentiality agreement. 
All information provided by the Sponsor and all data and information generated by the site as part of 
the study (other than a subject’s medical records) will be kept confidential by the PI and other site 

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74 
staff. This information and data will not be used by the PI or other site personnel for any purpose 
other than conducting the study.  
12.5. Publication 
IVAC will work with the PI and other relevant personnel at NIHE on the publication of the complete 
Phase 1/2 study outlined in this protocol in a timely fashion. Primary publication of the trial results 
will be shared between the NIHE and IVAC. Other individuals having input into the study justifying 
authorship will similarly be included in publication(s). Additional publications resulting from the 
analysis of the study data will be agreed between IVAC and the NIHE on a case-by-case basis but 
will generally include authors from both organizations. IVAC will be acknowledged in all 
publications as the Sponsor of the trial. 
If a written contract for the conduct of the study, which includes publication provisions inconsistent 
with this statement, is executed between IVAC and the study site, that contract’s publication 
provisions shall apply rather than this statement. 
 
13. QUALITY ASSURANCE AND QUALITY CONTROL 
13.1. General Considerations 
The study will be conducted in full compliance with the protocol and ICH GCP to provide public 
assurance that the rights, safety, and well-being of study subjects are protected, and that the clinical 
study data are credible. To ensure quality and standardization, the site will develop SOPs for key 
protocol procedures and conduct the study guided by the study and applicable site SOPs and other 
written guidelines. The site will also develop routine operational checks to verify that critical protocol 
requirements and procedures are executed correctly and completely at the time the work is being 
performed. Prior to study initiation, the Sponsor and the designated CRO will conduct training on the 
protocol and applicable SOPs for the study staff. 
The investigational site will provide direct access to all study-related documents, source 
data/documents, and reports for monitoring and auditing by the Sponsor, and inspection by regulatory 
authorities. 
13.2. External Monitoring 
Sponsor monitoring responsibilities will be provided by the CRO. A site initiation visit will be 
conducted prior to beginning the study, and monitoring will be conducted at initiation, during, and at 
closeout of the study by the study monitor or designee.  
During the course of the study, the monitor will assess site activities at intervals to verify compliance 
to the protocol; completeness, accuracy, and consistency of the data and study product accountability; 
adherence to protocol and regulatory obligations; and to ensure that conduct of the research follows 
GCP. The extent and frequency of the monitoring visits will be described in a separate Clinical 
Monitoring Plan developed prior to study initiation. The monitor should have access to subject 
medical records, study product accountability and other study-related records needed to verify the 
entries on the CRFs. 
The PI and the monitor will cooperate to ensure that any problems detected in the course of these 
monitoring visits, including EDC completion and query resolution, are resolved in a predefined time 

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75 
frame described in the Clinical Monitoring Plan. 
To ensure the quality of clinical data for all subjects, a clinical data management review will be 
performed on subject data received by the CRO. During this review, subject data will be checked for 
consistency, omissions, and any apparent discrepancies. In addition, the data will be reviewed for 
adherence to the protocol and GCP. To resolve any questions arising from the clinical data 
management review process, data queries and/or site notifications will be sent to the site for 
resolution as soon as possible and within the time frame described in the Clinical Monitoring Plan; all 
queries must be resolved prior to database lock. 
13.3. Independent Auditing 
Sponsor representatives may audit the study to ensure that study procedures and data collected 
comply with the protocol and applicable SOPs of the site and the CRO, and that data are correct and 
complete. The PI will permit auditors (employees of the Sponsor or an external company designated 
by the Sponsor) to verify source data validation of the regularly monitored clinical study. The 
auditors will compare the entries in the CRFs with the source data and evaluate the study site for its 
adherence to the clinical study protocol and GCP guidelines and applicable regulatory requirements. 
13.4. Regulatory Agency Auditing 
The PI must be aware that representatives from regulatory authorities may wish to inspect the CRFs 
and associated study records. The PI will notify the Sponsor within 24 hours following contact by a 
regulatory agency. The PI will make the relevant records available for inspection and will be 
available to respond to reasonable requests and audit queries made by authorized representatives of 
regulatory agencies. The PI will provide the Sponsor with copies of all correspondence that may 
affect the review of the current study or her/his qualification as PI in clinical studies conducted by the 
Sponsor. The Sponsor will provide any needed assistance in responding to regulatory audits or 
correspondence. 
 
 
14. OBLIGATIONS AND ROLES OF THE SPONSOR, PI, AND STUDY PERSONNEL 
This study will be conducted according to GCP as well in accordance with Ministry of Health 
regulations. The Sponsor will assure the trial is conducted in compliance with the protocol, GCP, and 
regulatory authority requirements. The Sponsor will provide the PI with the funding and information 
needed to conduct the trial properly, ensuring proper monitoring of trial activities, and that the trial is 
conducted in accordance with the general investigational plan and protocol contained in the 
submissions to the regulatory authorities. The Sponsor will ensure that the PI and regulatory 
authorities are immediately informed (within 24 hours of the Sponsor becoming aware) of significant 
new adverse effects or risks with respect to the study vaccine. The Sponsor will ensure that they will 
be immediately informed (within 24 hours of awareness) of any other safety concerns which could 
influence decisions regarding informed consent, enrollment and vaccination in this trial. 
The PI agrees to perform the research in strict accordance with this protocol, the ICH GCP (E6), as 
well as in conformity with local regulations regarding the conduct of clinical studies (see Statement of 
Compliance). 
In addition, the PI will follow local and institutional requirements including, but not limited to, 

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76 
investigational vaccines, clinical research, informed consent and ethics regulations. The Sponsor will 
provide notification to the PI of protocol and amendment approvals by regulatory authorities when 
applicable. Any modifications to the research protocol, the ICF, and/or change in PI will be 
submitted for review and approval to regulatory authorities per their guidelines. The PI may deviate 
from the protocol without prior approval only when the deviation is necessary to eliminate an 
apparent immediate hazard to the study subject. 
While the PI may delegate study duties to appropriate study personnel, the PI is ultimately 
responsible for the conduct of all aspects of the study. 
 
15. ETHICAL CONSIDERATIONS AND INFORMED CONSENT 
The study will be performed in accordance with SOPs generated and agreed between the Sponsor-
designated CRO and the PI. The CRO has the responsibility for ensuring the site has the appropriate 
SOPs to perform the study and the authority to defer to the site SOP rather than the CRO SOP when 
appropriate. These SOPs have been developed in accordance with ICH Guidelines for GCP E6 R2 
(2018), Directive 2001/20/EC, which are consistent with the Ethical Guidelines outlined in the 
Declaration of Helsinki (2013), thus ensuring protection of the subjects. The study will commence 
only after receipt of a favorable opinion from the EC listed in this protocol and Ministry of Health. 
15.1. Ethical Review 
Ethical review of this study for the clinical site will be jointly conducted by the Ministry of Health 
IRBand NIHE EC. The Sponsor will enter into a reliance agreement with ECs for ethical review. The 
PI is responsible for obtaining approval from the Ministry of Health IRBand NIHE EC, which will 
review and approve the protocol, the informed consent form, and any recruitment materials 
(advertising or informational material). This includes any modifications to these documents prior to, 
or during the study. Any change to the protocol or informed consent form must be reviewed and 
approved prior to implementation, except when necessary to eliminate apparent immediate hazard to 
study subjects. In such a case, the change must be later documented in an amendment and reported to 
the ECs as soon as possible. When a change involves only logistical or administrative aspects of the 
study (e.g., change of a telephone number), formal EC approval may not be required, but such 
amendments shall still be submitted to the ECs for information purposes, and the PI must provide the 
Sponsor with written confirmation that such logistical or administrative amendments have been 
submitted to the ECs. The PI will provide the Sponsor with a statement from the ECs confirming that 
the ECs are organized and operates according to GCP and applicable laws and regulations. The PI is 
also responsible for obtaining continuing review throughout the duration of the study in accordance 
with existing regulations 
15.2. Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the 
study and continues throughout the subject’s participation in the study. Before any study-
relatedactivities, the PI must ensure that the potential subject is fully informed about the objectives, 
procedures, potential risks, and potential benefits of study participation. 
Potential subjects will be provided with the EC-approved ICF, allowed ample time to read the 
consent form, encouraged to ask questions about the study, have their questions answered and thenbe 
given time to decide if they would like to participate in the study. If the subject is illiterate, there will 

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77 
be a witness or legally appropriate representative attending the consent process to assure the subject is 
properly consented. It will be emphasized that their participation is voluntary, and that they have the 
right to decline to participate or to discontinue from the study at any time without giving any reason 
and without compromising their other rights in any way. 
The PI must obtain the subject’s voluntary, signed and dated ICF before any study-related procedures 
are performed. Study staff must document the informed consent process. The original, signed ICF 
must be kept in the site study file. A copy of the informed consent document will be given to the 
subject for their records. 
15.3. Study-Related Injury 
IVAC will maintain product liability insurance to cover treatment for study-related injuries. IVAC 
will also maintain employer liability insurance or shall self-insure, as necessary, to meet its liability 
obligations under this protocol, as well as sufficient levels of all legally mandated insurance, 
including (at a minimum) professional liability coverage for the investigator, trial team, and all other 
employees, contractors, and agents providing services to this trial. As applicable, IVAC will maintain 
insurance to cover any general liability and product liability to meet its obligations under Vietnam 
law. 
15.4. Risk/Benefit 
There are certain symptoms and signs, systemic or injection site, which have historically 
been associated with immunization, and if they do occur, usually are of mild or moderate intensity 
and transient in nature. Consequently, in early clinical trials of investigational vaccines, these 
symptoms and signs are typically considered as risks and are solicited as potential AEs in the first 
week following immunization. In this trial, the solicited injection site AEs include pain, 
tenderness, swelling or induration, and erythema. The solicited systemic AEs are fever, headache, 
fatigue or malaise, myalgia, arthalgia, and nausea or vomiting. Since there may be unknown risks 
associated with the COVIVAC vaccine, all subjects will be monitored for any unsolicited AEs for 28 
days following study product administration and for any MAAEs or SAEs for the entire study period. 
All subjects will also be monitored for specific AESI; these include potential immune-mediated 
medical conditions, which may be associated with vaccination. In addition subjects will be closely 
monitored for adverse events associated with COVID-19 to identify, and treat if indicated, potential 
cases of COVID-19 during the trial, and to assess for possible vaccine-induced immune enhancement 
of disease.  
CpG 1018 is the adjuvant used in HEPLISAV-B vaccine, which was licensed by the US FDA in 
2018. HEPLISAV-B was well-tolerated and shown to have an adequate safety profile in clinical trials 
in adults.49 Common adverse reactions from HEPLISAV-B included injection site pain, erythema, 
and swelling, headache, malaise, myalgia, and fatigue. SAEs, autoimmune adverse events, and deaths 
were infrequent in the HEPLISAV-B clinical program and similar in frequency between HEPLISAV-
B and the active comparator (Engerix-B). No deaths have been considered by the investigator to be 
related to HEPLISAV-B. Interim analyses of an ongoing post-marketing study of over 30,000 
HEPLISAV-B recipients and more than 35,000 active comparator recipients have raised no safety 
concerns.  
Hypersensitivity reactions may occur following the administration of any vaccine, including licensed 
vaccines, which in rare circumstances may be life-threatening. All subjects will be informed in the 
ICF of this possibility following study vaccine administration and will be observed for a minimum of 

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78 
30 minutes following study vaccine administration. Appropriate emergency medical treatment will be 
available in case of severe immediate reactions, such as anaphylaxis. Subjects with a known 
hypersensitivity to any component of the study vaccine, or a history of hypersensitivity to any 
vaccine, will be excluded from the study. 
Blood drawing- and venipuncture-associated risks may include minor bleeding or bruising at the 
venous access site, mild discomfort, upset stomach, dizziness, light-headedness, syncope, or very 
rarely infection. Blood samples will only be drawn by trained staff members using aseptic technique, 
and medical assistance will be available in case of any complications. Subjects will be informed of 
these risks in the ICF and will be in a seated or supine position during blood draws. 
No benefits can be guaranteed to subjects for their participation in this research study. Subjects who 
participate in this study may benefit from the clinical assessments (e.g., medical history, physical 
examination, and routine clinical safety laboratory tests) conducted at screening and during the 
study, including the screening for infections. If the subject is found to have any newly diagnosed 
medical condition or infection, the investigator will ensure that the subject is provided with 
appropriate and adequate referrals within the health care system. The information gained from this 
study may be useful in the development of a safe and effective vaccine to prevent COVID-19 for 
which there is currently no licensed vaccine. Subjects may gain from knowing that they have been 
involved in this development process. The known risks of participation in this study are believed to 
be outweighed by the value of the information to be gained. 
15.5. Subject Confidentiality 
Every effort will be made to protect subject privacy and confidentiality. Personal identifiers will not 
be included in any study reports. Medical records containing identifying information will be made 
available for review when the study is monitored by the Sponsor or an authorized regulatory agency. 
Direct access may include examining, analyzing, verifying, and reproducing any records and reports 
that are important in the evaluation of the study. 
All study-related information will be stored securely at the study site. All subject information will be 
stored in locked file cabinets in areas with access limited to study staff. Data collection, process, and 
administrative forms, and other reports will be identified only by a unique trial-related subject 
identification code (subject/randomization ID) to maintain subject confidentiality. Laboratory reports 
may include the name and date of birth of the subject to minimize the risk of errors in the busy 
clinical laboratories. All local databases will be secured with password-protected access systems. 
Forms, lists, logbooks, appointment books, and any other listings that link subject ID numbers to 
other identifying information will be stored in a separate, locked file in an area with limited access. 
Subjects’ study information will not be released without their written permission, except as necessary 
for monitoring, or as required/permitted by law/regulatory authorities. 
15.6. Reimbursement 
Pending EC approval, subjects will be compensated for their time and effort in this study. The study 
ICF will state the plan for reimbursement. Subjects will not be charged for study injections, research 
clinic visits, research-related examinations, or research-related laboratory tests. 
15.7. Storage of Specimens 

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79 
Stored study research samples will be labeled by a code that only the study site can link to the study 
subject. All stored research samples will be logged into a secure database and any use documented. 
Samples may be stored at the clinical sites and laboratories included in the contact cover page of this 
protocol, to complete the analyses required to meet study primary, secondary and exploratory 
analyses. As a part of the informed consent process, subjects will be informed of and asked to agree 
to long-term storage of specimens for use in future, related research. 
When samples are no longer needed for the purposes of the study, they will be kept or destroyed, 
depending on whether subjects consent to remaining samples being used in future research. Their use 
will be governed by a repository plan that is mutually agreeable to the Sponsor and NIHE. No genetic 
testing will be done on the samples. 
 

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80 
16. APPENDICES 
16.1. 
Appendix 1:  Solicited Injection Site and Systemic Reactions Toxicity Grading Table 
Reaction to 
Injectable 
Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain/ 
Tenderness 
Does not 
interfere with 
activity  
Some interference 
with activity OR 
Repeated use of non-
narcotic pain reliever 
> 24 hours 
Significant; prevents 
daily activity OR  
Any use of narcotic 
pain reliever 
Emergency room 
(ER) visit or 
hospitalization 
Erythemaa 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm and/or 
ulceration OR 
secondary infection 
OR phlebitis OR 
sterile abscess OR 
drainage  
Necrosis or 
exfoliative dermatitis  
Swelling/ 
Indurationa 
2.5 – 5 cm and 
does not 
interfere with 
activity 
5.1 – 10 cm OR 
Interferes with 
activity 
> 10 cm OR prevents 
daily activity and/or 
ulceration OR 
secondary infection 
OR phlebitis OR 
sterile abscess OR 
drainage  
Necrosis  
Temperature 
(oral) 
38.0 – 38.4°C 
100.4 – 
101.1°F 
38.5 – 38.9°C 
101.2 – 102.0°F 
39.0 – 40°C 
102.1 – 104°F 
> 40°C 
> 104°F 
Headache  
No interference 
 with activity  
Some interference  
with activity OR 
Repeated use of 
nonnarcotic pain 
reliever >24 hours 
Significant; prevents  
daily activity OR  
Any use of 
narcotic pain reliever  
 
 
ER visit or 
hospitalization  
Fatigue/ 
Malaise  
No interference 
with activity  
Some interference  
with activity  
Significant; prevents 
daily activity  
ER visit or  
hospitalization  
Myalgia 
 
No interference 
with activity  
Some interference  
with activity  
Significant; prevents  
daily activity  
ER visit or  
hospitalization  
Arthralgia 
No interference 
with activity  
Some interference  
with activity  
Significant; prevents  
daily activity  
ER visit or  
hospitalization  
Nausea/ 
Vomiting 
No 
interference 
with activity  
Some interference 
with activity  
Prevents daily activity 
OR Requires 
outpatient IV 
hydration  
ER visit or 
hospitalization for 
hypotensive shock 

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81 
a For erythema and swelling/induration, longest diameter should be noted in centimeters. Swelling/induration 
should be evaluated and graded using the functional scale as well as the actual measurement. 
 
The grading scales for local and systemic AEs have been derived from Guidance for Industry, Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
U.S. Department of Health and Human Services, FDA, CBER, September 2007( 
https://www.fda.gov/media/73679/download) and the Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events (Version 2.1, July 2017) from the US NIH 
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf). 
 
 
 

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82 
16.2. 
Appendix 2:  Vital Signs Toxicity Grading Table 
Vital Signsa  
Mild 
(Grade 1)  
Moderate 
(Grade 2)  
Severe  
(Grade 3)  
Potentially Life Threatening  
(Grade 4)  
Tachycardia – beats per  
minute  
101 – 115  
116 – 130  
> 130  
Hospitalization for arrhythmia  
Bradycardia –beats per  
minuteb 
50 – 54  
45 – 49  
< 45  
ER visit or hospitalization for 
arrhythmia  
Hypertension (systolic)   
– mm Hg 
141 – 150  
151 – 165  
> 165  
ER visit or hospitalization for 
malignant hypertension  
Hypertension (diastolic) 
– mm Hg  
91 – 99  
100 – 105  
> 105  
ER visit or hospitalization for 
malignant hypertension 
Hypotension (systolic)  
– mm Hg  
85 – 89  
80 – 84  
< 80  
ER visit or hospitalization for 
hypotensive shock  
Respiratory Rate –  
breaths per minute  
21 – 23  
24 – 27  
> 27  
Intubation  
a Subject should be at rest for all vital sign measurements.  
b Grade 1 bradycardia or grade 1 tachypnea will not be considered an abnormality for this study, unless judged 
to be clinically significant by the PI in consultation with the Sponsor 
 
The grading scales for abnormal vital signs have been derived from Guidance for Industry, Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. 
Department of Health and Human Services, FDA, CBER, September 2007. 
 
 

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83 
16.3. Appendix 3: Serum and Hematology Toxicity Grading Table 
Serum 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Creatinine  
(mg/dL) 
1.1 – 1.3 x ULN 
> 1.3 – 1.8 x ULN 
OR increase of  
 > 0.3 above 
baseline 
> 1.8 – < 3.5 x 
ULN OR increase 
of 
 1.5 – < 2.0 x above 
baseline 
≥ 3 .5 x ULN 
OR increase of  
> 2.0 x above 
baseline 
Liver function tests 
– AST, ALT 
increased 
1.25 – < 2.5 x ULN 
2.5 – <5.0 x ULN 
5.0  – < 10.0 x 
ULN 
≥ 10.0 x ULN 
Total bilirubin  
1.1 – < 1.6 x ULN 
1.6 – < 2.6 x ULN 
2.6 – < 5.0 x ULN 
≥ 5.0 x ULN 
Hematology 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Hemoglobin 
[Female] 
(g/dL) 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin 
[Male] 
 (g/dL) 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5 
OR  
Hemoglobin, 
change from 
baseline value 
(g/dL) 
1.0 – 1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC, increased 
(cell/mm3) 
10,800 – 15,000 
15,001 – 20,000 
20,0001 – 25,000 
> 25,0000 
WBC, decreased  
(cell/mm3) 
2,500 – 3,400 
1,500 – 2,499 
1,000 – 1,499 
< 1,000 
Platelets, decreased 
(cell/mm3) 
100,000 – <125,000 
50,000 – <100,000 
25,000 – < 50,000 
< 25,000 
Abbreviation: ULN = upper limit of normal range 
Note: the laboratory values provided in this table serve as guidelines and are dependent upon institutional 
normal parameters. 
The grading scales for laboratory abnormalities have been derived from Guidance for Industry, Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, 
U.S. Department of Health and Human Services, FDA, CBER, September 2007, and the Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (Version 2.1, July 2017) from 
the US NIH. 
 
 

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84 
16.4. Appendix 4: Potential Immune-Mediated Medical Conditions (PIMMC) 
Categories  
Diagnoses  
Neuroinflammatory Disorders:  
Acute disseminated encephalomyelitis (including 
site specific variants: e.g., non-infectious 
encephalitis, encephalomyelitis, myelitis, 
myeloradiculomyelitis), cranial nerve disorders 
including paralyses/paresis (e.g., Bell’s palsy), 
generalized convulsion, Guillain-Barre syndrome 
(including Miller Fisher syndrome and other 
variants), immune-mediated peripheral 
neuropathies and plexopathies (including chronic 
inflammatory demyelinating polyneuropathy, 
multifocal motor neuropathy and polyneuropathies 
associated with monoclonal gammopathy), 
myasthenia gravis, multiple sclerosis, narcolepsy, 
optic neuritis, transverse myelitis, uveitis  
Musculoskeletal and Connective Tissue Disorders:  Antisynthetase syndrome, dermatomyositis, 
juvenile chronic arthritis (including Still’s disease), 
mixed connective tissue disorder, polymyalgia 
rheumatic, polymyositis, psoriatic arthropathy, 
relapsing polychondritis, rheumatoid arthritis, 
scleroderma (including diffuse systemic form and 
CREST syndrome), spondyloarthritis (including 
ankylosing spondylitis, reactive arthritis [Reiter's 
Syndrome] and undifferentiated spondyloarthritis), 
systemic lupus erythematosus, systemic sclerosis, 
Sjogren’s syndrome  
Vasculidities:  
Large vessels vasculitis (including giant cell 
arteritis such as Takayasu's arteritis and temporal 
arteritis), medium sized and/or small vessels 
vasculitis (including polyarteritis nodosa, 
Kawasaki's disease, microscopic polyangiitis, 
Wegener's granulomatosis, Churg–Strauss 
syndrome [allergic granulomatous angiitis], 
Buerger’s disease [thromboangiitis obliterans], 
necrotizing vasculitis and anti-neutrophil 
cytoplasmic antibody [ANCA] positive vasculitis 
[type unspecified], Henoch-Schonlein purpura, 
Behcet's syndrome, leukocytoclastic vasculitis)  
Gastrointestinal Disorders:  
Crohn’s disease, celiac disease, ulcerative colitis, 
ulcerative proctitis  
Hepatic Disorders:  
Autoimmune hepatitis, autoimmune cholangitis, 
primary sclerosing cholangitis, primary biliary 
cirrhosis  

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
85 
 
ANew onset only 
This list was derived from Tavares Da Silva F, De Keyser F, Lambert PH, Robinson WH, Westhovens R, 
Sindic C. Optimal approaches to data collection and analysis of potential immune mediated disorders in 
clinical trials of new vaccines. Vaccine. 2013 Apr 3;31(14):1870-6.  
Categories  
Diagnoses  
Renal Disorders:  
Autoimmune glomerulonephritis (including 
Immunoglobulin A nephropathy, 
glomerulonephritis rapidly progressive, 
membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and 
mesangioproliferative glomerulonephritis  
Cardiac Disorders:  
Autoimmune myocarditis/cardiomyopathy  
Skin Disorders:  
Alopecia areata, psoriasis, vitiligo, Raynaud’s 
phenomenon, erythema nodosum, autoimmune 
bullous skin diseases (including pemphigus, 
pemphigoid and dermatitis herpetiformis), 
cutaneous lupus erythematosus, morphoea, lichen 
planus, Stevens-Johnson syndrome, Sweet’s 
syndrome  
Hematologic Disorders: 
 
 
Metabolic Disorders:  
 
 
 
Other Disorders:  
 
Autoimmune hemolytic anemia, autoimmune 
thrombocytopenia, antiphospholipid syndrome, 
thrombocytopenia  
Autoimmune thyroiditis, Grave’s or Basedow’s 
disease, Hashimoto thyroiditisA, diabetes mellitus 
type 1, Addison’s disease 
Goodpasture syndrome, idiopathic pulmonary 
fibrosis, pernicious anemia, sarcoidosis 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
86 
16.5. Appendix 5: Adverse Events Specific to COVID-19 Disease 
Body System  
Diagnoses  
Immunologic  
Enhanced disease following immunization 
Multisystem inflammatory syndrome in children 
(MIS-C)  
Respiratory  
Acute respiratory distress syndrome (ARDS)  
Cardiac  
Acute cardiac injury including:  
• Microangiopathy  
• Heart failure and cardiogenic shock  
• Stress cardiomyopathy  
• Coronary artery disease  
• Arrhythmia  
• Myocarditis, pericarditis  
Hematologic  
Coagulation disorder  
• Deep vein thrombosis  
• Pulmonary embolus  
• Cerebrovascular stroke  
• Limb ischemia  
• Hemorrhagic disease  
• Thrombotic complications  
Renal  
Acute kidney injury  
Gastrointestinal  
Liver injury  
Neurologic  
Guillain Barré Syndrome 
Anosmia, ageusia 
Meningoencephalitis  
Dermatologic  
Chilblain-like lesions 
Single organ cutaneous vasculitis  
Erythema multiforme  
 
This listing is based on Safety Platform for Emergency Vaccines (SPEAC) D2.3 Priority List of 
Adverse Events of Special Interest: COVID-19, V2.0 Date May 25, 2020. 
https://brightoncollaboration.us/wp-content/uploads/2020/06/SPEAC_D2.3_V2.0_COVID-
19_20200525_public.pdf 
 

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87 
16.6. Appendix 6: Template of interim study report for transition to Phase 2 
 
1. Cover pages (according to the CSR template by MOH VN) 
- 
Study title, protocol number 
- 
Key individuals and institution involving the study. 
- 
Timeline for study implementation for Phase 1 
2. Protocol synopsis  
3. Brief Investigational plan 
4. Study Participant disposition until D43 
- 
Enrollment/screening counts: total participants screened/enrolled/screen failures/Early 
termination 
- 
Screening failure summary: illegible, withdrawn consent, study no longer for enrollment, 
others. 
- 
Study progress: number of subject attending ICF/screening, V1/D1, V2/D8, V3/D29, V4/D36, 
V5/D43, V6/D57 visits 
- 
Protocol deviations 
5. Demographic and key baseline characteristics 
6. Immunogenicity analysis till cutoff date 
- 
Humoral (functional) immune response 
7. DSMB safety recommendation (unblinded) 
8. Safety analysis till cutoff date (blinded) 
- 
Local solicited AEs 
- 
Systemic solicited AEs 
- 
Unsolicited AEs  
- 
SAEs 
- 
MAAEs 
- 
AESI  
9. Discussion and recommendation of two selected doses for Phase 2  
 
 

Study Protocol:   Version: 2.0 dated Aug 03, 2021_ IVAC  
88 
16.7. Appendix 7: References 
 
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adolescents-with-covid-19 
22 Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and Outcomes 
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