Evaluation of the Immunogenicity, Safety, and Tolerability of a Single Dose of ABNCoV2 Vaccine in Adult Subjects Previously Vaccinated for SARS-CoV-2: a Phase 3 Trial in Two Parts
Phase: PHASE3
Conditions: COVID-19 Disease
Sponsor: Bavarian Nordic

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Clinical Trial Protocol 
 
EudraCT # 2021-005504-36 
NCT05329220 
IND 28466 
 
 
Evaluation of the Immunogenicity, Safety, and 
Tolerability of a Single Dose of ABNCoV2 Vaccine in 
Adult Subjects Previously Vaccinated for 
SARS-CoV-2: a Phase 3 Trial in Two Parts—
Randomized, Double-blind, Active Controlled and 
Open-label, Single-arm 
 
 
30-Jun-2023 
 
 
 
 
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Table of Contents 
Table of Contents...................................................................................................... 2 
List of Tables ............................................................................................................. 8 
List of Figures ........................................................................................................... 8 
1 
General Information ........................................................................................ 9 
1.1 Abbreviations .................................................................................................... 9 
1.2 Definitions ........................................................................................................ 11 
1.3 Protocol Synopsis ............................................................................................ 12 
1.4 Trial Schedule ................................................................................................. 21 
1.5 Responsibilities ................................................................................................ 24 
2 
Background Information and Scientific Rationale ..................................... 26 
2.1 Introduction to SARS-CoV-2 ........................................................................ 26 
2.2 ABNCoV2 Vaccine ......................................................................................... 26 
2.2.1 
Nonclinical Studies with ABNCoV2 Vaccine ............................................ 27 
2.2.2 
Clinical Trials with ABNCoV2 Vaccine .................................................... 28 
2.3 Scientific Rationale ......................................................................................... 33 
2.4 Risk/Benefit Assessment ................................................................................ 34 
2.4.1 
Risks .............................................................................................................. 34 
2.4.2 
Potential Benefits ......................................................................................... 35 
2.4.3 
Risk/Benefit Balance ................................................................................... 35 
3 
Trial Design ..................................................................................................... 36 
3.1 Part A: Randomized, Double-blind, Active Controlled Component ......... 36 
3.2 Part B: Open-label, Single-arm Component ................................................ 36 
3.3 End of Study / Study Completion ................................................................. 37 
4 
Objectives ........................................................................................................ 37 
4.1 Primary Objective .......................................................................................... 37 
4.2 Secondary Objectives ..................................................................................... 37 
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4.3 Safety Objectives ............................................................................................. 37 
4.4 Exploratory Objectives .................................................................................. 38 
5 
Endpoints and Population-level Summaries ............................................... 38 
5.1 Primary Endpoint ........................................................................................... 38 
5.2 Secondary Endpoints ...................................................................................... 38 
5.3 Safety Endpoints ............................................................................................. 39 
5.4 Exploratory Endpoints ................................................................................... 39 
6 
Study Population ............................................................................................ 40 
6.1 Inclusion Criteria ............................................................................................ 40 
6.2 Exclusion Criteria ........................................................................................... 40 
6.3 Inclusion of Older Subjects ............................................................................ 40 
6.4 Selection of Subjects ....................................................................................... 40 
6.5 Recruitment and Retention ........................................................................... 40 
7 
Study Intervention ......................................................................................... 41 
7.1 Vaccine Dosage and Administration ............................................................. 41 
7.2 Subject Discontinuation ................................................................................. 41 
8 
Schedule of Procedures by Visit ................................................................... 42 
8.1 Screening Visit ................................................................................................ 42 
8.2 Active Phase .................................................................................................... 42 
8.2.1 
Visit 1 ............................................................................................................ 42 
8.2.2 
Visit 2 ............................................................................................................ 43 
8.2.3 
Visit 3 ............................................................................................................ 43 
8.2.4 
Visit 4 / End of Active Phase ...................................................................... 44 
8.3 Follow-up Phase .............................................................................................. 44 
8.4 Unscheduled Visit ........................................................................................... 44 
9 
Investigational Medicinal Product ............................................................... 44 
9.1 Production, Packaging and Labeling ............................................................ 44 
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9.2 Shipment, Storage and Handling .................................................................. 45 
9.3 Preparation ...................................................................................................... 45 
9.4 Accountability and Disposal .......................................................................... 45 
10 
Assessment of Immunogenicity ..................................................................... 46 
10.1 Humoral Immune Response .......................................................................... 46 
10.2 Cellular Immune Response ............................................................................ 46 
10.3 Nucleocapsid Protein Antibody Testing ....................................................... 47 
10.4 Future Use of Lab Specimens ........................................................................ 47 
11 
Safety and Reactogenicity.............................................................................. 47 
11.1 Definitions ........................................................................................................ 47 
11.1.1 Medical History ........................................................................................... 47 
11.1.2 Adverse Events ............................................................................................ 48 
11.1.3 Unsolicited AEs ............................................................................................ 48 
11.1.4 Solicited AEs ................................................................................................ 48 
11.1.5 Serious Adverse Events, Serious Adverse Reactions, Adverse 
Events of Special Interest, and Medically Attended Adverse Events ..... 49 
11.2 Relevant Medical History .............................................................................. 50 
11.3 Prior and Concomitant Medication .............................................................. 50 
11.4 Prohibited Medications .................................................................................. 50 
11.5 Physical Examination ..................................................................................... 51 
11.5.1 Complete Physical Examination ................................................................ 51 
11.5.2 Targeted Physical Examination ................................................................. 51 
11.6 Vital Signs ........................................................................................................ 52 
11.7 Unsolicited AEs ............................................................................................... 52 
11.8 Solicited AEs ................................................................................................... 54 
11.8.1 Solicited Local AEs ...................................................................................... 54 
11.8.2 Solicited General AEs ................................................................................. 55 
11.9 Adverse Events of Special Interest ................................................................ 56 
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11.9.1 General AESI Definitions ........................................................................... 56 
11.9.2 Myocarditis and Pericarditis ...................................................................... 57 
11.10 Confirmed COVID-19 Infection with Severe Manifestations or 
Resulting in Critical Illness ............................................................................ 58 
11.11 Safety Laboratory Measurements ............................................................... 58 
11.12 Cardiac Assessment....................................................................................... 60 
11.13 Pregnancy ....................................................................................................... 60 
11.14 Reporting ........................................................................................................ 60 
11.14.1 Reporting of SAEs and AESIs .................................................................... 60 
11.14.2 Reporting of MAAEs................................................................................... 61 
11.14.3 Reporting of Pregnancies ............................................................................ 61 
12 
Statistical Considerations .............................................................................. 62 
12.1 Randomization Procedure and Blinding Consideration, Part A Only ...... 62 
12.2 Sample Size Calculation ................................................................................. 62 
12.2.1 Part A ............................................................................................................ 62 
12.2.2 Part B ............................................................................................................ 63 
12.3 Multiplicity ...................................................................................................... 63 
12.4 Variables .......................................................................................................... 64 
12.5 Analysis Populations ...................................................................................... 64 
12.6 Primary Analysis ............................................................................................ 64 
12.6.1 Primary Estimand ....................................................................................... 64 
12.6.2 Primary Analysis Methods ......................................................................... 65 
12.6.3 Sensitivity and Supportive Analyses .......................................................... 65 
12.6.4 Subgroup Analyses ...................................................................................... 66 
12.7 Secondary Analyses ........................................................................................ 66 
12.7.1 Secondary Estimand.................................................................................... 66 
12.7.2 Secondary Analysis Methods ...................................................................... 67 
12.7.3 Sensitivity and Supportive Analyses .......................................................... 67 
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12.7.4 Subgroup Analyses ...................................................................................... 67 
12.8 Exploratory Endpoints ................................................................................... 67 
12.9 Analyses of Safety ........................................................................................... 68 
12.10 Timing of Analyses ........................................................................................ 69 
12.10.1 Primary Analysis ......................................................................................... 69 
12.10.2 Final Analysis ............................................................................................... 69 
13 
Ethical Aspects................................................................................................ 69 
13.1 Ethical and Legal Regulations ....................................................................... 69 
13.2 Approval by IEC/IRB .................................................................................... 69 
13.3 Data and Safety Monitoring .......................................................................... 70 
13.3.1 Data Monitoring Committee ...................................................................... 70 
13.3.2 Stopping Rules ............................................................................................. 70 
13.4 Confidentiality and Data Protection ............................................................. 71 
14 
Informed Consent ........................................................................................... 71 
15 
Electronic Case Report Forms and Retention of Records ......................... 72 
15.1 Electronic Case Report Forms ...................................................................... 72 
15.2 Retention of Records ...................................................................................... 72 
16 
Monitoring of the Trial .................................................................................. 73 
16.1 Monitoring Plan .............................................................................................. 73 
16.2 Protocol Deviations ......................................................................................... 74 
17 
Audits and Inspections ................................................................................... 74 
18 
Responsibility of the Investigator ................................................................. 74 
19 
References ....................................................................................................... 76 
20 
Appendices ...................................................................................................... 79 
Appendix 1: Toxicity Scale for Laboratory Values ............................................. 79 
Appendix 2: Grading Scale for Lymphadenopathy............................................. 80 
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Appendix 3: Myocarditis and Pericarditis Scale, Case Definitions for 
COVID-19 Adverse Events of Special Interest, Brighton 
Collaboration .................................................................................................. 81 
Appendix 4: Adverse Event Follow-up Questionnaire — Inflammatory 
Cardiac Disorders ........................................................................................... 84 
Appendix 5: Signature Page ................................................................................... 92 
Appendix 6: Summary of Changes for Amendment#1 
to the Clinical Trial Protocol ......................................................................... 95 
Appendix 7: Summary of Changes for Amendment#2 
to the Clinical Trial Protocol ......................................................................... 99 
Appendix 8: Summary of Changes for Amendment#3 
to the Clinical Trial Protocol ....................................................................... 101 
Appendix 9: Summary of Changes for Amendment#4 
to the Clinical Trial Protocol ....................................................................... 103 
Appendix 10: Summary of Changes for Amendment#5 
to the Clinical Trial Protocol ....................................................................... 104 
Appendix 11: Summary of Changes for Amendment#6 
to the Clinical Trial Protocol ....................................................................... 109 
Appendix 12: Summary of Changes for Amendment#7 
to the Clinical Trial Protocol ....................................................................... 117 
 
 
 
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List of Tables
Table 1
Overall Summary of Adverse Events in Seropositive Subjects During the 
Active Trial Period ................................................................................................. 33
Table 2
Grading of Local Symptoms from the Subject’s Memory Aid .......................... 55
Table 3
Grading of General Symptoms from the Subject’s Memory Aid ...................... 56
Table 4
Brighton Collaboration Publications of COVID-19 AESI Case 
Definitions ............................................................................................................... 81
Table 5
Description of Changes from Edition 1.0 to Edition 2.0 ..................................... 95
Table 6
Description of Changes from Edition 2.0 to Edition 3.0 ..................................... 99
Table 7
Description of Changes from Edition 3.0 to Edition 4.0 ................................... 101
Table 8
Description of Changes from Edition 5.0 to Edition 6.0 ................................... 104
Table 9
Description of Changes from Edition 6.0 to Edition 7.0 ................................... 109
List of Figures
Figure 1
Structural Elements of ABNCoV2: 
 
.......................................................................................................... 27
Figure 2
Neutralizing Antibody Titers from Phase 1 by Dose .......................................... 29
Figure 3
Neutralizing Antibody Titers for SARS-CoV-2 Wildtype and Alpha, Beta 
and Delta Variants ................................................................................................. 29
Figure 4
Neutralizing Antibody Titers Against the Wuhan Strain at Baseline, 
Week 1, and Week 2 in Initially Seropositive Subjects Who Received 100 
g of ABNCoV2 ...................................................................................................... 30
Figure 5
Interferon-Ȗ (Th1) ELISpot for SARS-CoV-2 RBD of Index Virus and 
Variants of Concern (data from 100 g dose group of Phase 2) ........................ 31
Figure 6 
Interleukin-4 (Th2) ELISpot for SARS-CoV-2 RBD of Index Virus and 
Variants of Concern (data from 100 g dose group of Phase 2) ........................ 32
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1
General Information 
1.1
Abbreviations
ACE2
angiotensin-converting enzyme 2
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphokinase
ALT
alanine amino transferase
AST
aspartate aminotransferase
ȕ-HCG
beta-human chorionic gonadotropin
BMI
body mass index
BN
Bavarian Nordic
CBER
Center for Biologics Evaluation and Research
CI
confidence interval
COVID-19
coronavirus disease 2019
CRA
clinical research associate
CRO
contract research organization
CSPV
clinical safety and pharmacovigilance
CSR
clinical study report
CTS
clinical trial site
cVLP
capsid virus-like particles
DMC
data monitoring committee
EAP
end of active phase
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunoassay
ELISpot
enzyme-linked immuno spot assay
EU
European Union
EUA
emergency use authorization
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
FDA
US Food and Drug Administration
FU
follow-up
GCP
good clinical practice
GMT
geometric mean titer
HBsAG
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
investigator brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
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IgG 
immunoglobulin G 
IM 
intramuscular 
IMP 
investigational medicinal product 
IND 
investigational new drug application 
IRB 
institutional review board 
IU 
international units 
LLOQ 
lower limit of quantification 
MAAE 
medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCT 
ClinicalTrials.gov national clinical trials number 
NHP 
nonhuman primates 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PI 
principal investigator 
PRNT 
plaque reduction neutralization test 
QTc 
QT interval corrected 
RBD 
receptor-binding domain 
SAE 
serious adverse event 
SAR 
serious adverse reaction 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SUSAR 
suspected unexpected serious adverse reactions 
SOP 
standard operating procedure 
US 
United States 
VOC 
variant of concern 
WOCBP 
women of childbearing potential 
 
 
 
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1.2 Definitions 
active control 
arm 
Comirnaty (tozinameran, BNT162b2, Pfizer/BioNTech) SARS-CoV-2 
vaccination. 
active trial 
phase 
The period from the trial vaccination up to and including the end of active 
trial phase (EAP) visit at 28 to 35 days after trial vaccination. 
locally 
authorized 
SARS-CoV-2 
vaccines 
“Locally authorized” SARS-CoV-2 vaccines include any vaccine that has 
received market approval or emergency use authorization (EUA) in the 
country of enrollment at the time of screening for eligibility. Subjects can be 
eligible if they previously received investigational vaccines that have since 
been authorized for emergency use or granted full market licensure.  
completed 
primary 
vaccination 
regimen 
Completed primary vaccination regimen with a locally authorized 
SARS-CoV-2 vaccine. “Completed primary vaccination regimen” includes 
full primary vaccination as described in the labeling of the initial vaccine, 
with no less than 3 weeks between the doses; completed primary vaccination 
also includes any mix/match series of 2 doses of any locally authorized 
SARS-CoV-2 vaccine, or a single dose of any locally authorized COVID-19 
vaccine in subjects who previously had a confirmed COVID-19 infection. 
completed 
primary plus 
boost 
vaccination 
Completed primary plus boost vaccination with locally authorized 
SARS-CoV-2 vaccine(s). “Completed primary plus boost vaccination” 
includes full primary vaccination as described above plus a boost vaccination 
administered at least 2 months after the last primary dose. The boost dose 
may be the same or different vaccine as received in the primary vaccination 
regimen. 
end of active 
trial phase 
(EAP)  
The visit (also Visit 4) at the end of the active trial phase, approximately 
28 to 35 days after trial vaccination. In the event of early withdrawal of a 
subject from the trial during the active trial phase, the EAP visit will be the 
visit at which the final safety endpoints for the trial are collected. 
end of study/ 
study 
completion 
The final date on which data are collected (i.e., the last subject’s last visit or 
scheduled assessment). 
follow-up 
period 
The period after the active trial phase, up to approximately 6 months after 
trial vaccination. 
SARS-CoV-2 
index virus 
Wuhan wild type isolate of the severe acute respiratory coronavirus 2. 
trial period 
The active trial phase plus the follow-up period. 
trial 
vaccination 
Part A, randomized component: Single boost or re-boost vaccination with 
either ABNCoV2 or Comirnaty 
Part B, single-arm component: Single boost or re-boost with ABNCoV2 
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1.3 Protocol Synopsis 
Title 
Evaluation of the Immunogenicity, Safety and Tolerability of a Single 
Dose of ABNCoV2 Vaccine in Adult Subjects Previously Vaccinated 
for SARS-CoV-2: a Phase 3 Trial in Two Parts—Randomized, 
Double-blind, Active Controlled and Open-label, Single-arm 
Clinical Phase 
Phase 3 
Sponsor 
Bavarian Nordic A/S 
Philip Heymans Alle 3 
2900 Hellerup 
Denmark 
Trial Identifiers 
Sponsor trial code: ABNCoV2-03 
EudraCT #: 2021-005504-36 
ClinicalTrials.gov #: NCT05329220 
IND #: 28466 
Trial Design 
This trial is composed of a randomized, double-blind, active controlled 
component (Part A) and an open-label, single-arm component (Part B) 
conducted in parallel.  
 
Part A is designed to compare vaccination with a single 100 g dose 
of ABNCoV2 to a single 30 g adult booster dose of Comirnaty 
(active control) in adult subjects who either previously completed 
primary vaccination (Cohort 1) or have already received 1 booster dose 
(Cohort 2) of SARS-CoV-2 locally authorized vaccine(s), and whose 
last locally authorized SARS-CoV-2 vaccination was at least 3 months 
prior to the screening visit. Subjects will be randomized in a 1:1 ratio 
to receive either ABNCoV2 or Comirnaty. 
 
Part B is designed to collect ABNCoV2 safety and tolerability data 
from a larger population of adult subjects, as well as additional 
immunogenicity data from a subset. Part B involves vaccination with 
the same single 100 g dose of ABNCoV2 in the same population of 
adult subjects as the randomized component, and subjects will 
similarly be enrolled into 2 cohorts according to whether they have 
completed primary vaccination only or primary plus booster 
vaccination. 
Trial Duration 
Approximately 28 weeks for each subject. 
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Sites and Countries 
Part A: 13 sites in Belgium and Denmark 
Part B: 45 sites in the United States  
   Immunogenicity subset: Select US sites 
Vaccination Dose 
Part A: Either a single 100 g dose of ABNCoV2 vaccine or a single 
30 g adult boost dose of Comirnaty (tozinameran, BNT162b2) 
vaccine  
Part B: Single 100 g dose of ABNCoV2 vaccine 
Vaccine 
Administration 
ABNCoV2 and Comirnaty are administered intramuscularly into the 
deltoid muscle of the non-dominant arm.  
Part A: To blind both subjects and trial staff, preparation of the trial 
vaccine will be performed by a local, unblinded site staff member, e.g., 
a local pharmacist. 
Sample Size 
Part A: Healthy adult subjects, who have previously completed 
primary vaccination with locally authorized SARS-CoV-2 vaccine(s) at 
least 3 months prior to the screening visit, will be enrolled into 
2 cohorts as specified below: 
x Cohort 1: subjects who previously completed primary vaccination 
only  
x Cohort 2: subjects who have completed primary vaccination and 
have received 1 booster vaccination 
For each cohort, the targeted enrollment is 500 subjects. 
Based on data from the ABNCoV2 phase 2 trial, we assume a common 
standard deviation of 0.52 for log10 transformed neutralizing antibody 
titers. We further assume 10% of the population will be non-evaluable 
due to dropout or compromised serum samples. When the sample size 
is 500 (450 evaluable) with a 1:1 randomization ratio, a one-sided 
0.0125 significance level test will have 90% power to reject the null 
hypothesis for Cohort 1 or Cohort 2 that ABNCoV2 is inferior to 
Comirnaty, with a non-inferiority margin of 0.67. 
Part B: A total of up to 3000 healthy adult subjects, who have 
previously completed vaccination with locally authorized 
SARS-CoV-2 vaccine(s) at least 3 months prior to the screening visit, 
will be enrolled into 2 cohorts as specified below: 
x Cohort 1 (at least 250 subjects): subjects who previously 
completed primary vaccination only 
x Cohort 2 (at least 250 subjects): subjects who have completed 
primary vaccination and have received 1 booster vaccination 
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The sample size for Part B is not based on a statistical hypothesis test, 
but rather on the number of subjects exposed to ABNCoV2 considered 
adequate for safety population analyses and may be adjusted 
depending on enrolment in Part A. A total of 3000 subjects (for 
example, 2500 from Part B plus 500 from Part A who will receive 
ABNCoV2) would allow for 95% power to detect an adverse event 
with an incidence rate as low as 0.1%. 
The immunogenicity subset in Part B will consist of approximately 
200 to 250 subjects in each cohort. This subset sample size is based on 
feasibility alone, i.e., the number of participating sites and consenting 
subjects. 
Randomization and 
Blinding 
Part A only: At Visit 1, subjects will be randomized in a 1:1 ratio to 
receive ABNCoV2 or Comirnaty (active control) single dose 
vaccination. Randomization will be stratified within each cohort by age 
group (<65 years versus 65 years) and previous vaccination regimen.  
 
An unblinded member of the local site team will handle the trial 
vaccine, while the subject and the staff involved in subject evaluation 
and follow-up will remain blinded. Immunogenicity assessments will 
be performed by laboratory personnel who have no knowledge of 
treatment assignment and no access to the trial data. The clinical 
operational and analysis teams also will be blinded to treatment 
assignment until the time of the primary and key secondary endpoint 
analyses.  
Primary Objective 
Part A: To assess non-inferiority, or superiority, of vaccination with 
ABNCoV2 compared to Comirnaty in terms of neutralizing antibodies 
against the SARS-CoV-2 index virus (Wuhan wild type isolate), in 
Part A Cohort 1 (adult subjects who previously completed primary 
vaccination at least 3 months prior to the screening visit) and Part A 
Cohort 2 (adult subjects who have completed primary vaccination and 
have received 1 booster vaccination). 
Key Secondary 
Objective 
Part A: To assess in Part A cohorts the non-inferiority, or superiority, 
of vaccination with ABNCoV2 compared to Comirnaty in terms of 
neutralizing antibodies against SARS-CoV-2 variants of concern 
(VOCs) circulating at time of the trial.  
Other Secondary 
Objective 
Part B: To assess neutralizing antibody titers against the 
SARS-CoV-2 index virus after vaccination with ABNCoV2 in the 
immunogenicity subsets of Part B Cohort 1 and Cohort 2. 
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Safety Objectives 
Part A: To assess the safety and tolerability of the ABNCoV2 vaccine 
compared to Comirnaty in previously vaccinated adult subjects in 
Part A (both cohorts). 
 
Parts A and B: To assess the safety and tolerability of the ABNCoV2 
vaccine in previously vaccinated adult subjects (all subjects receiving 
ABNCoV2). 
Exploratory 
Objectives 
To compare total binding immunoglobulin G (IgG) antibodies against 
the SARS-CoV-2 index virus after vaccination with ABNCoV2 or 
Comirnaty in subsets of each Part A cohort.  
 
To explore the kinetics of SARS-CoV-2-specific humoral responses in 
subsets of each Part A cohort. 
 
To explore SARS-CoV-2-specific cellular responses at 1 week after 
ABNCoV2 vaccination within the immunogenicity subsets of each 
Part B cohort. 
 
To compare neutralizing antibodies against the SARS-CoV-2 index 
virus at 2 weeks after vaccination with ABNCoV2 between cohorts in 
Part A and Part B. 
Primary Endpoint 
Population-level 
Summary 
Part A: Geometric mean titer (GMT) of neutralizing antibodies 
against the SARS-CoV-2 index virus at 2 weeks after trial vaccination, 
in each Part A cohort. 
Success Criterion for 
Primary Endpoint 
If the sample size requirement is met in each of the Part A cohorts 
(minimum of 400 evaluable per cohort), the success criterion will be 
applied in each of the cohorts as specified below. In the event the 
sample size requirement is not met in one of the cohorts, the success 
criterion will only be applied to the cohort meeting the sample size 
requirement, and results for the under-recruited cohort will be 
descriptive only. 
 
Ratio of GMTs at 2 weeks after trial vaccination, for ABNCoV2 
vaccine compared to Comirnaty vaccine, is within the non-inferiority 
margin of 0.67; specifically, the success criterion will be met within 
each cohort if the lower bound of the 2-sided 97.5% CI of the GMT 
ratio is 0.67. 
 
If the non-inferiority criterion is met, a superiority test will be carried 
out based on the same type I error level. 
 
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If the non-inferiority criterion is met in at least one cohort, supportive 
analyses will include assessing non-inferiority or superiority in 
Cohort 1 and Cohort 2 combined. 
Key Secondary 
Endpoint Population-
level Summary 
Part A: GMT of neutralizing antibodies against the SARS-CoV-2 
VOCs circulating at time of the trial, at 2 weeks after trial vaccination, 
in the Part A cohort(s) in which the primary endpoint success criterion 
is met.  
Success Criterion for 
Key Secondary 
Endpoint 
If both Cohort 1 and Cohort 2 are tested for and meet the success 
criterion for the primary endpoint, VOCs will be tested in the cohort 
with the higher number of evaluable subjects, followed by the cohort 
with the smaller number of evaluable subjects if the success criterion is 
met in at least one of the tested VOCs in the cohort tested first. In the 
event only one cohort meets the success criterion for the primary 
endpoint, VOCs will be formally tested for the successful cohort only.  
 
Ratios of GMTs for the VOCs at 2 weeks after trial vaccination, for 
ABNCoV2 vaccine compared to Comirnaty vaccine, will be tested 
using the non-inferiority margin of 0.67 as was used for the primary 
endpoint. The result will be based on the lower limit of a two-sided CI 
with coverage determined based on the number of VOCs circulating at 
the time of the trial. A Bonferroni correction will be employed for the 
simultaneous non-inferiority tests to control the trial-wide type I error. 
 
If the non-inferiority criterion is met, a superiority test will be carried 
out based on the same type I level. 
 
If the non-inferiority criterion is met in at least one cohort and one 
VOC, supportive analyses will include assessing non-inferiority or 
superiority in Cohort 1 and Cohort 2 combined. 
Other Secondary 
Endpoint Population-
level Summary 
Part B: GMTs of neutralizing antibodies against the SARS-CoV-2 
index virus at 2 weeks after trial vaccination in subjects receiving 
ABNCoV2 in the immunogenicity subsets of Part B Cohort 1 and 
Cohort 2.  
Safety Endpoint 
Population-level 
Summaries 
Part A: For all subjects receiving ABNCoV2 compared to those 
receiving Comirnaty, the percent who report the safety endpoints listed 
below. 
Parts A and B: For all subjects receiving ABNCoV2, the percent who 
report the safety endpoints listed below. 
 
Safety endpoints: 
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x 
Serious adverse events (SAEs) or adverse events of special 
interest (AESIs) assessed as related to trial vaccine during the 
entire trial period, which includes both the active trial phase and 
follow-up. 
x 
Grade 3 or higher adverse events (AEs) assessed as related to 
trial vaccine in the 8-day period starting with the day of 
vaccination.  
x 
SAEs, AESIs, or medically attended AEs (MAAEs), regardless 
of relationship, during the active trial phase. 
x 
SAEs, AESIs, or MAAEs, regardless of relationship, during the 
entire trial period. 
x 
Grade 3 or higher AEs assessed as related to trial vaccine during 
the active trial phase. 
x 
Solicited local AEs in the 8-day period starting with the day of 
vaccination. 
x 
Solicited general AEs in the 8-day period starting with the day of 
vaccination. 
Exploratory 
Endpoint Population-
level Summaries 
Geometric mean fold increases, from baseline to post-baseline time 
points after trial vaccination, in neutralizing antibodies against the 
SARS-CoV-2 index virus. 
 
Geometric mean fold increases, from baseline to post-baseline time 
points after trial vaccination, in neutralizing antibodies against the 
SARS-CoV-2 VOCs circulating at time of the trial. 
 
GMT of total binding IgG antibodies against the SARS-CoV-2 index 
virus at 2 weeks after trial vaccination in subsets of each Part A cohort. 
 
Geometric mean fold increases, from baseline to post-baseline time 
points after trial vaccination, in total binding IgG antibodies against 
the SARS-CoV-2 index virus in subsets of each Part A cohort. 
 
GMT of neutralizing antibodies against the SARS-CoV-2 index virus 
and the SARS-CoV-2 VOCs circulating at time of the trial, at 1, 4, 13 
and 26 weeks after trial vaccination in subsets of each Part A cohort. 
 
Geometric means of SARS-CoV-2-specific T cells secreting 
interferon-J / interleukin-4 at 1 week after ABNCoV2 vaccination 
within the immunogenicity subsets of each Part B cohort. 
Trial Halting Criteria  Data Monitoring Committee will review the following to determine 
whether a temporary halting or termination of the trial is warranted:  
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x 
A serious AESI or other SAE with an at least reasonable 
possibility of a causal relationship to the administration of 
ABNCoV2 or Comirnaty vaccine. 
x 
An unexpected Grade 3 or higher adverse event (e.g., a systemic 
reaction or lab toxicity) with an at least reasonable possibility of 
a causal relationship to the trial vaccination. 
Trial Population: 
Inclusion Criteria 
 
1. Age 18 years at screening. 
2. Documented, previous completion of a primary vaccination 
regimen with locally authorized SARS-CoV-2 vaccine(s) or 
completion of primary plus 1 boost vaccination (see definition of 
completed primary vaccination regimen and completed primary 
plus boost vaccination in Section 1.2), with last vaccination at least 
3 months before screening. “Locally authorized” SARS-CoV-2 
vaccines are those that have received market approval or EUA in 
the country of enrollment. 
3. Absence of acute medical illness, significant physical exam 
findings, or laboratory abnormalities, as determined by the 
investigator. 
4. Informed consent, provided by the subject prior to performance of 
any trial-specific procedures; the subject has read, signed, and 
dated an informed consent form (ICF), having been advised of the 
risks and benefits of the trial in a language understood by the 
subject.  
5. Body mass index (BMI) 18.5 and <40. 
6. For female subjects of childbearing potential (WOCBP) and male 
subjects who are sexually active with a WOCBP, agreement to use 
an effective method of birth control from at least 30 days prior to 
administration of the vaccine until 30 days after the vaccination. A 
woman is considered of childbearing potential unless post-
menopausal (defined as 12 months without a menstrual period at 
screening) or surgically sterilized (bilateral oophorectomy, bilateral 
tubal ligation, hysterectomy). Acceptable contraception methods 
are restricted to abstinence (only acceptable if refraining from 
heterosexual intercourse during the period of 30 days prior to 
administration of the vaccine until 30 days after the vaccination), 
double barrier contraceptives, vasectomy, intrauterine 
contraceptive devices, or licensed hormonal products. 
7. For WOCBP, a negative serum pregnancy test at screening. 
8. Negative tests for human immunodeficiency virus antibody 
(anti-HIV), hepatitis B surface antigen (HBsAG), and antibody to 
hepatitis C virus (HCV). 
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Trial Population: 
Exclusion Criteria 
 
1. History of COVID-19 infection within the last 3 months before 
screening. 
2. Previous vaccination with a SARS-CoV-2 vaccine other than those 
mentioned in inclusion criterion #2. 
3. Positive test for SARS-CoV-2 infection at screening. 
4. Breastfeeding with intent to continue. 
5. Acute or chronic medical condition that, in the opinion of the 
investigator, would render the trial procedures unsafe or would 
interfere with the evaluation of the responses. 
6. History of myocarditis or pericarditis. 
7. History of or active autoimmune disease. History of Guillain-Barré 
syndrome or Reye’s syndrome. Persons with vitiligo or thyroid 
disease taking thyroid replacement are not excluded.  
8. Known or suspected impairment of immunologic functions 
including, but not limited to, known immunodeficiency syndrome. 
9. History of malignancy other than squamous cell or basal cell skin 
cancer, unless there has been surgical excision at least 6 months 
prior to screening that is considered to have achieved cure. 
Subjects with history of skin cancer must not be vaccinated at the 
previous tumor site.  
10. Laboratory parameters (such as complete blood count, serum 
biochemistry including aspartate aminotransferase [AST], alanine 
amino transferase [ALT], alkaline phosphokinase [ALP], bilirubin, 
or creatinine values), pulse rate, or blood pressure outside normal 
range at screening and deemed clinically relevant by the 
investigator. 
11. Clinically significant mental disorder not adequately controlled by 
medical treatment. 
12. Active or recent history (within 6 months before screening) of 
chronic alcohol abuse, or illicit drug abuse. 
13. History of allergic disease or reactions likely to be exacerbated by 
any component of the vaccine. 
14. History of anaphylaxis or severe allergic reaction to any vaccine. 
15. History of any vaccinations or plan to receive any vaccinations 
with a live vaccine within 30 days prior to or after trial vaccination. 
16. History of any vaccinations or plan to receive any vaccinations 
with a non-live vaccine within 14 days prior to or after trial 
vaccination. 
17. Recent blood donation (including platelets, plasma and red blood 
cells) within 4 weeks prior to screening, or planned blood 
donations during the active phase of the trial. 
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18. Chronic systemic administration (defined as more than 14 days) of 
>5 mg prednisone (or equivalent)/day, or any other immune-
modifying drugs during a period starting 3 months prior to 
administration of the vaccine and ending 4 weeks after vaccination. 
The use of topical, inhaled, ophthalmic and nasal glucocorticoids is 
allowed. 
19. History of organ transplantation, whether or not accompanied by 
chronic immunosuppressive therapy. 
20. Administration or planned administration of immunoglobulins 
and/or any blood products during a period starting 3 months prior 
to administration of the vaccine and ending 4 weeks after 
vaccination. Receipt of packed red blood cells given for an 
emergency indication in an otherwise healthy person, and not 
required as ongoing treatment is not exclusionary (for example 
packed red blood cells given in emergency during an elective 
surgery). 
21. Use of any investigational or non-registered drug or vaccine other 
than the trial vaccine within 30 days preceding the administration 
of trial vaccine, or planned administration of such a drug or 
vaccine throughout the trial. 
22. Involvement in this trial as site personnel. 
23. Known bleeding disorder that, in the opinion of the investigator, 
would contraindicate intramuscular injection. 
Trial Population: 
Inclusion of Subjects 
65 Years of Age 
Sites will be instructed to pursue a target of 25% of enrollment to be 
subjects 65 years of age in Part A and 33% of enrollment to be 
subjects 65 years of age in Part B. The target is to have 
approximately 1000 subjects 65 years of age who receive ABNCoV2. 
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1.4 Trial Schedule 
Visit 
SCR 
V1 
V2 
V3 
V4/ 
EAP 
FU1 
(phone) 
FU2 
FU3 
Day / Visit +… Days 
V1 
-14 – -1 
Day 1 
V1a  
+5–7 
V1a 
+12–16 
V1a 
+28–35 
V1a 
+56–70 
V1a 
+91–105 
V1a 
+182–196 
Target week 
-2 
0 
1 
2 
4 
8 
13 
26 
Target month 
 
0 
 
 
1 
2 
3 
6 
Informed consent 
X 
 
 
 
 
 
 
 
Eligibility assessment 
X 
X 
 
 
 
 
 
 
Demographics collection 
X 
 
 
 
 
 
 
 
Medical history review 
X 
 
 
 
 
 
 
 
Physical examination 
(including height, weight, BMI)b 
X 
 
 
 
 
 
 
 
ECGb 
X 
 
 
 
 
 
 
 
Evaluation of vital signsb 
X 
X 
X 
X 
X 
 
X 
X 
Recording of prior and concomitant 
medication 
X 
X 
X 
X 
X 
 
 
 
Blood draw for safety labsb 
X 
 
 
X 
(X)c 
 
 
 
Pregnancy test for WOCBPd 
X 
X 
 
 
X 
 
 
 
Counseling on avoidance of pregnancy for 
WOCBPe  
X 
X 
 
 
 
 
 
 
Hep-B, HCV, HIV test  
X 
 
 
 
 
 
 
 
SARS-CoV-2 infection PCR test 
X 
 
(X)f 
(X)f 
(X)f 
 
(X)f 
(X)f 
Targeted physical exam (including 
auscultation of the heart and lungs)b 
 
X 
X 
X 
X 
 
X 
X 
AE/SAE/SAR/AESI/MAAE recording 
X 
Xg 
X 
X 
X 
Xh 
Xh 
Xh 
Blood collection for serum antibody titers 
and nucleocapsid protein antibody testingi, 
Part A 
 
Xi,j 
X 
Xi 
X 
 
Xi 
Xi 
Blood collection for serum antibody titers 
and nucleocapsid protein antibody testing, 
Part B immunogenicity subsetk 
 
Xj 
 
X 
 
 
 
 
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Visit 
SCR 
V1 
V2 
V3 
V4/ 
EAP 
FU1 
(phone) 
FU2 
FU3 
Day / Visit +… Days 
V1 
-14 – -1 
Day 1 
V1a  
+5–7 
V1a 
+12–16 
V1a 
+28–35 
V1a 
+56–70 
V1a 
+91–105 
V1a 
+182–196 
Target week 
-2 
0 
1 
2 
4 
8 
13 
26 
Target month 
 
0 
 
 
1 
2 
3 
6 
Blood collection for PBMCs, Part B 
immunogenicity subsetk 
 
Xj 
X 
 
 
 
 
 
Randomizationl 
 
X 
 
 
 
 
 
 
Handout of memory aid 
 
X 
 
 
 
 
 
 
Trial vaccine administration and subject 
observation (30ௗminutes) 
 
X 
 
 
 
 
 
 
Recording of immediate AEs 
 
X 
 
 
 
 
 
 
Review/collection of memory aidm 
 
 
X 
(X) 
(X) 
 
(X) 
(X) 
Examination of injection site 
 
 
X 
 
 
 
 
 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; BMI = body mass index; EAP = end of active phase visit; ECG = 
electrocardiogram; FU1/FU2/FU3 = follow-up visits; Hep-B = hepatitis B; HCV = hepatitis C virus; HIV = human immune deficiency virus; MAAE = 
medically attended adverse event; PBMC = peripheral blood mononuclear cells; PCR = polymerase chain reaction; SAE = serious adverse event; SAR = 
serious adverse reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SCR = Screening; V1-V4 = active phase, Visits 1 to 4; 
WOCBP = woman of childbearing potential.  
X: mandatory; (X): if indicated/if applicable 
Part A: randomized component; Part B: single-arm component 
a The visit windows for V2, V3, V4/EAP, FU1, FU2, and FU3 will be calculated based upon the date of vaccination (V1) with either ABNCoV2 or 
Comirnaty. 
b If clinically indicated, additional safety measures can be taken at any other trial visits or at unscheduled visits. Auscultation of the heart and lungs is to be 
performed at any physical examinations to check specifically for signs of any heart condition or respiratory disorders. 
c Only for subjects who discontinued during the trial and are coming for EAP visit to obtain final safety data. 
d At SCR, a serum pregnancy test must be performed. At V1 and EAP, a urine pregnancy test will be performed. 
e Review of acceptable contraceptive methods and recent menstrual history with WOCBP. 
f At any time during the trial starting after vaccination if clinically indicated, e.g., in the presence of COVID-19 typical symptoms. 
g AESIs and MAAEs are not collected until vaccine has been received at visit 1. 
h During the follow-up period, data collection will be limited to SAEs, AESIs, and MAAEs, and any unsolicited AEs from the active trial period that are not 
yet resolved. 
i Nucleocapsid protein antibody testing will be done only on samples collected at V1, V3, FU2, and FU3. 
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j Any blood collected for serum or PBMC samples at V1 must be collected before vaccination. Baseline serum samples will also be tested for antibodies 
suggestive of previous COVID-19 infection. 
k Immunogenicity subset blood samples will be collected at select US sites. 
l Only for subjects enrolled in Part A. 
m If symptoms persist at 7 days after vaccination, daily symptoms and temperature will continue to be measured and documented each day until resolved. 
Memory aid will be collected once it is complete. 
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1.5
Responsibilities
Sponsor
Bavarian Nordic A/S
Philip Heymans Alle 3
2900 Hellerup
Denmark
Phone (direct office)
E-mail
info@bavarian-nordic.com
Project Leader
Phone
E-mail
Medical Monitor (
)
Medical Monitor
(BN)
E-mail
Trial Statistician
Phone
E-mail
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CRO Project 
Manager
Phone
E-mail
Laboratory
(Immunogenicity 
testing)
Phone
E-mail
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2
Background Information and Scientific Rationale
2.1
Introduction to SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which causes 
coronavirus disease 2019 (COVID-19), is an ongoing worldwide public health emergency. 
SARS-CoV-2 is not only highly infectious, but infections may lead to humoral immune responses 
with low virus neutralizing capacity (Chen et al., 2020, Robbiani et al., 2020, Wu et al., 2020).
SARS-CoV-2 entry into cells occurs through interaction of the virus spike receptor-binding 
domain (RBD) with the angiotensin-converting enzyme 2 (ACE2) protein on human cells. Upon 
binding, ACE2 acts as a receptor, and human proteases are recruited to mediate cell entry (Shang 
et al., 2020a).
In convalescent COVID-19 patients, despite generally low humoral responses, neutralizing 
antibodies specific to the RBD of SARS-CoV-2 are recurrently found (Robbiani et al., 2020).
Interestingly, SARS-CoV-2 may be more effective in evading an effective immune response than 
SARS-CoV (the coronavirus that caused the severe acute respiratory syndrome outbreak of 2003)
because the SARS-CoV-2 spike more frequently assumes a conformational state that hides the 
spike RBD (Shang et al., 2020b, Walls et al., 2020, Wrapp et al., 2020). Therefore, displaying the 
spike RBD of SARS-CoV-2 in a manner that facilitates recognition by the immune system is 
likely to be protective against COVID-19.
2.2
ABNCoV2 Vaccine
The unique cVLP display platform of the ABNCoV2 vaccine is also referred to as a capsid-like 
particle and can be modified to present different antigens. 
 cVLPs have also been shown to 
significantly increase murine antibody responses in terms of titer, avidity, and functionality 
(Thrane et al., 2016, Tissot et al., 2010, Janitzek et al., 2016, Pastori et al., 2012).
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2.2.1 Nonclinical Studies with ABNCoV2 Vaccine
The immunogenicity of ABNCoV2 has been demonstrated in mice (Fougeroux et al., 2021) and 
in non-human primates (NHP). A single IM administration of 100 g ABNCoV2 induced 
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SARS-CoV-2 neutralizing antibodies in NHP at comparable levels as found in human 
convalescent samples, while neutralizing antibody titers induced by 15 Pg ABNCoV2 remained 
below convalescent levels. A second administration of 15 Pg or 100 Pg ABNCoV2 led to a 
>50-fold increase in titers. While 15 Pg ABNCoV2 administered 2 times to NHP resulted in 
significantly reduced lung viral load after SARS-CoV-2 challenge compared to nonvaccinated 
control animals, the higher dose of 100 Pg ABNCoV2 administered 2 times resulted in complete 
protection, as evidenced by the majority of animals being completely free of virus in lung and 
also in nasal swabs.  
The safety and good tolerability of 100 Pg ABNCoV2 (adjuvanted in a squalene in water 
emulsion) administered 2 or 3 times in rabbits was demonstrated in a Good Laboratory Practice-
compliant repeat dose toxicity and local tolerance study, and no safety concerns for human use 
were raised. 
The ABNCoV2 dose administered to rabbits translates to a human equivalent dose based on body 
surface area (FDA, 2005) of 774 Pg for a 60 kg human; this provides a safety margin that is 
>7× higher than a 100 Pg human dose. Even when the use of different methods by different 
laboratories to determine the ABNCoV2 protein concentration is taken into account, a potentially 
lower dose of 70 Pg instead of 100 Pg used in the toxicity study translates to a human equivalent 
dose of 542 Pg for a 60 kg human and still provides a safety margin that is >5x higher than a 
100 Pg human dose. Further, the number of vaccine applications (3) suggests further safety for 
the 1 to 2 administrations used in the human studies (see Section 2.2.2). 
See further details in the current effective ABNCoV2 IB.  
2.2.2 Clinical Trials with ABNCoV2 Vaccine 
A first-in-human trial was conducted in 45 subjects (COUGH-1, EudraCT no. 2020-004621-22/ 
NCT04839146). In a predefined dose escalation, SARS-CoV-2-naïve subjects received up to 
70 g of the ABNCoV2 vaccine in this phase 1 trial. Preliminary safety results did not show any 
relevant safety findings. Final results from this trial are not yet available at the time of completion 
of this protocol, but the currently available data indicate that humoral immune responses were 
elicited at all dose levels after completion of the 2-dose schedule in the initially seronegative 
population. While there was a dose-response effect between 6 g and 25 g, for the dose levels 
between 25 g and 70 g a dose saturation was observed (see Figure 2) based on preliminary 
data from a small subset of subjects (3 subjects in each of the 6, 12, and 25 g groups and 
6 subjects in each of the 50 and 70 g groups). With the serum samples of the subjects in the 
25 g dose group, a broad immune response against the variants of concern (VOCs) Alpha, Beta 
and Delta was observed in the neutralization assay (see Figure 3). For further dose justification, 
please refer to Section 2.2.1. 
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Figure 2
Neutralizing Antibody Titers from Phase 1 by Dose 
Titers obtained 14 days after second dose in 2-dose schedule in initially seronegative subjects.
Abbreviations: HCS = human convalescent sera; PRNT50 = 50% plaque reduction neutralization test.
Figure 3
Neutralizing Antibody Titers for SARS-CoV-2 Wildtype and Alpha, Beta and Delta 
Variants
Titers obtained 14 days after second dose in 2-dose schedule at 25 g per dose.
Abbreviations: HCS = human convalescent sera; PRNT50 = 50% plaque reduction neutralization test.
An open-label phase 2 study (ABNCoV2-01, EudraCT no. 2021-001393-31, NCT05077267) to 
evaluate safety, tolerability and immunogenicity of the ABNCoV2 vaccine is in progress. The 
trial is evaluating a homologous prime-boost regimen in seronegative subjects with the 100 Pg
high dose supported by animal studies. The trial also is evaluating both a 100 Pg single dose 
boost regimen and a 50 Pg single dose boost regimen in subjects who had either completed their 
primary vaccination or had confirmed SARS-CoV-2 infection at least 3 months prior. The intent 
is to evaluate whether the 2-dose primary regimen elicits an immune response that is as good as 
expected, based on the available nonclinical and phase 1 data, and whether a single dose boost 
regimen elicits a comparably high immune response in seropositive subjects.
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In addition, the phase 2 trial also serves as the basis for the dose decision between 50 and 100 g 
in this phase 3 trial.  
Preliminary humoral immunogenicity data for the 100 g single dose seropositive group from 
phase 2 has been analyzed by the time of completion of this protocol. Overall, across the 
101 subjects with data from 2 weeks after boost vaccination, there was a 15.1-fold increase over 
baseline in geometric mean titer (GMT) of neutralizing antibodies against the SARS-CoV-2 
index virus. Subgroup analysis showed a 39.7-fold GMT increase over baseline in those subjects 
with a baseline titer below the lower limit of quantification (LLOQ), a 7.1-fold GMT increase 
over baseline for those subjects with a baseline antibody titer above the LLOQ but below 
319 IU/mL (the median among those above the LLOQ), and a 2.2-fold GMT increase over 
baseline in those subjects with a baseline antibody titer at or above the median (see Figure 4). 
Figure 4 
Neutralizing Antibody Titers Against the Wuhan Strain at Baseline, Week 1, and 
Week 2 in Initially Seropositive Subjects Who Received 100 g of ABNCoV2 
 
Abbreviations: GMT = geometric mean titer; LLOQ = lower limit of quantification; NT = neutralizing titer. 
Preliminary data from the 50 g dose group of the phase 2 trial suggest a similar immunogenicity 
response to a single boost administration overall, with some slight trends towards higher fold 
increases with the 100 g dose, particularly in subjects who were primed with mRNA-based 
vaccines. The tolerability was roughly comparable between the 50 and 100 g dose groups. For 
further details on the 50 g results of phase 2, please refer to the IB. 
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SARS-CoV-2-specific T-cell responses, e.g., SARS-CoV-2-specific T cells secreting 
interferon-J /interleukin-4 upon restimulation, were assessed in the Phase 2 trial, using enzyme-
linked immuno spot technique (ELISpot). 
Results of the cellular immunogenicity analysis using interferon-J and interleukin-4 ELISpot 
showed a clearly Th1-focused boost response, with a broad and consistent response across all 
VOCs tested. Importantly, the ratio of Th1 to Th2 increased after administration of the 
ABNCoV2 boost vaccination for all VOCs. The results of the interferon-J and interleukin-4 
ELISpot analysis for the 100 g dose group of the Phase 2 trial are displayed in Figure 5 and 
Figure 6. 
Figure 5 
Interferon-Ȗ (Th1) ELISpot for SARS-CoV-2 RBD of Index Virus and Variants of 
Concern (data from 100 g dose group of Phase 2) 
 
Trial Week
GMC: 35.7
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S-RBD omicron
GMC: 32.9
135.7
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S-RBD delta
GMC: 29.1
129.3
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S-RBD beta
GMC: 31.5
128.1
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S-RBD alpha
GMC: 36.7
127.6
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S-RBD Wuhan
Baseline
Week 1
Baseline
Week 1
Baseline
Week 1
Baseline
Week 1
Baseline
Week 1
1
10
100
1000
10000
Cell Counts (SFU/10^6 PBMCs)
DocuSign Envelope ID: B668B9DC-A299-48F2-8894-D0352DD0D3C2

ABNCoV2 
 
Clinical Trial Protocol 
ABNCoV2-03 
Edition 8.0 
 
 
Bavarian Nordic 
Restricted Business Proprietary 
Page 32 of 119 
 
Figure 6  
Interleukin-4 (Th2) ELISpot for SARS-CoV-2 RBD of Index Virus and Variants of 
Concern (data from 100 g dose group of Phase 2) 
 
The preliminary safety data from phase 2 as of 15-Feb-2022 are presented below. Summary 
safety data for the active trial phase (4 weeks following vaccination) are presented in Table 1 for 
Groups 2 and 3 (the 2 dose groups of seropositive subjects). The preliminary data show that the 
solicited local and general vaccine side effects that occurred in 30% or more of subjects were 
injection site pain (79.9%), fatigue (45.0%), headache (43.2%), myalgia (36.1%), and injection 
site induration and erythema (30.8% each). The most commonly reported unsolicited AEs were 
nasopharyngitis (10), headache (5), oropharyngeal pain (4), and rhinitis, dizziness, diarrhea, and 
COVID-19 disease (3 occurrences each). (At this time, a Topline Interim Clinical Study Report 
[CSR] only is available.)  
There were 2 serious adverse events (SAEs) reported in the phase 2 study, both of which were 
assessed not to be related to trial vaccine. One event of metatarsal fracture and repair occurred in 
an elderly subject subsequent to a fall during their follow-up phase. The second was an event of a 
slipped cervical disc, which also occurred during follow-up. The subject underwent corrective 
surgery, and the SAE resolved.  
The Topline Interim Clinical Safety Report presented AESIs from the entire vaccinated phase 2 
trial population. A total of 11 AESIs were reported by 6 subjects; all were non-serious. There 
were 4 events of ageusia, 5 of anosmia, and 2 of thrombocytopenia. Only the 2 events of 
thrombocytopenia were assessed as related to the trial vaccine; they were mild grade, clinically 
Trial Week
GMC: 3.6
6.2
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S-RBD omicron
GMC: 3.6
6.6
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S-RBD delta
GMC: 3.7
7.4
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GMC: 3.6
6.8
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S-RBD alpha
GMC: 3.9
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S-RBD Wuhan
Baseline
Week 1
Baseline
Week 1
Baseline
Week 1
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Week 1
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Week 1
1
10
100
1000
Cell Counts (SFU/10^6 PBMCs)
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non-significant and transient, and they resolved without any treatment administered to subjects. 
The sponsor in agreement with the data monitoring committee (DMC) concluded that those cases 
represented minor fluctuations slightly below the reference range. An overall look at all platelet 
counts of all subjects throughout the trial confirmed that there was no trend toward declines in 
platelet counts. Therefore, no safety signal with regards to thrombocytopenia was confirmed. 
(Note: one of the cases of thrombocytopenia occurred in a Group 1 [initially seronegative] 
subject and is not included in Table 1.) 
Table 1 
Overall Summary of Adverse Events in Seropositive Subjects During the Active Trial 
Period 
 
Group 2a 
(N = 103) 
n (%) [Events] 
Group 3b 
(N = 66) 
n (%) [Events] 
Overall 
(N = 169) 
n (%) [Events] 
All AEs 
88 (85.4) [411] 
60 (90.9) [264] 
148 (87.6) [675] 
SAEs 
0 
0 
0 
AEs leading to withdrawal 
0 
0 
0 
Solicited local AEs 
82 (79.6) [179] 
56 (84.8) [124] 
138 (81.7) [303] 
Solicited local AEs Grade 3c 
5 (4.9) [5] 
5 (7.6) [5] 
10 (5.9) [10] 
Solicited general AEs 
72 (69.9) [190] 
41 (62.1) [110] 
113 (66.9) [300] 
Solicited general AEs Grade 3c, 
related 
13 (12.6) [29] 
4 (6.1) [13] 
17 (10.1) [42] 
Unsolicited AEs, related 
5 (4.9) [5] 
7 (10.6) [10] 
12 (7.1) [15] 
Unsolicited AEs Grade 3d, related 
0 
0 
0 
AESIse, related 
0 
1 (1.5) [1] 
1 (0.6) [1] 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; N = number of subjects in the 
Safety Analysis Set for the group of interest; n = number of subjects experiencing the event; SAE = serious 
adverse event. 
Data are not final; the data cutoff date is 15-Feb-2022. Data are presented for Groups 2 and 3 only (the two dose 
groups of seropositive subjects), as these are the topline study results to support use as a booster vaccine, and 
active phase data for Group 1 are not yet available. 
a Group 2 = Seropositive, 1 dose 100 g 
b Group 3 = Seropositive, 1 dose 50 g 
c Solicited AE grading based on trial-specific definitions for solicited local and general AEs 
d Unsolicited AE grading based on Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials. 
e AESIs are adopted as per the Safety Platform for Emergency vACcines (SPEAC) Project generated list of AESI 
for safety monitoring. 
For further details about phase 1 and phase 2 preliminary results, please refer to the IB. 
2.3 Scientific Rationale 
Despite the recent approval of several SARS-CoV-2 vaccines using different technologies, such 
as mRNA-based or adenovirus-vectored vaccines, there is still substantial spread of COVID-19 
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disease and related disease burdens. These burdens include fatal outcomes as well as the need for 
social distancing measures, causing a high economic and societal impact. 
The recent emergence of variant strains with yet unknown susceptibility to the currently available 
vaccines highlights the potential need for continuous adaptation of vaccines and the necessity to 
administer re-vaccinations (boosts) in populations considered at relevant risk.  
In developed countries, large parts of the population have obtained at least an initial 
SARS-CoV-2 vaccination regimen. Therefore, the medical need is expected to be for boost 
vaccinations for previously vaccinated subjects in order to maintain or adapt immunity to 
continuously circulating strains of SARS-CoV-2. Indeed, boost vaccinations have already been 
demonstrated to increase waning neutralizing antibody titers (Atmar et al., 2021, Munro et al., 
2021). This phase 3 trial is designed to test ABNCoV2 in the boost setting in two parallel parts. 
The first is a randomized, double-blind, non-inferiority comparison of ABNCoV2 100 ȝg to an 
active control group that will receive a standard adult booster dose of Comirnaty 
(Pfizer/BioNTech), an authorized SARS-CoV-2 vaccine. The second is an open-label, single-arm 
trial of ABNCoV2 100 ȝg. 
Based on results from the phase 2 trial of ABNCoV2, the single 100 g dose was selected as the 
appropriate phase 3 dose, due to its slight trend towards higher fold increases versus the 50 g 
dose in seropositive subjects, as well as its comparable reactogenicity.  
Comirnaty was chosen for the active control in the randomized component because mRNA 
SARS-CoV-2 vaccines were the first to be specifically authorized in the boost setting, and 
because certain European governments have agreed to make it available for this research. The 
analysis of Part A will provide comparison to a vaccine authorized in the boost setting and for 
which prior clinical trial data are available. 
2.4 Risk/Benefit Assessment 
2.4.1 Risks 
Based on the available data obtained in the nonclinical rabbit toxicology study and in the phase 1 
and 2 clinical trials, the 100 ȝg dose level planned for this phase 3 trial is not expected to cause 
any major risks. 
One suspected unexpected serious adverse reaction (SUSAR) of basal cell carcinoma was 
reported from phase 1 (COUGH-1) in a subject with a history of basal cell carcinoma and 
melanoma. In this subject, following 2 doses of ABNCoV2, 1 dose of Janssen COVID-19 
vaccine was administered as well.  
Overall safety data for ABNCoV2 is limited and preliminary, as the phase 1 and phase 2 studies 
are not yet completed. However, based on the currently available data (see Section 2.2.2), local 
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and systemic side effects are overall in line with the expected safety profile of already licensed 
COVID-19 vaccines. 
Myocarditis and pericarditis have so far not been observed in the phase 1 and phase 2 clinical 
development program of ABNCoV2. However, available data regarding myocarditis or 
pericarditis reported in individuals vaccinated with some licensed COVID-19 vaccines containing 
the S antigen strongly support a plausible causal relationship to the vaccines and have warranted 
inclusion of a warning statement and additional safety information about these events in EUA 
Fact Sheets and labeling of those approved vaccines. 
Blood drawing may cause discomfort, bruising, light-headedness, or fainting. Rarely, a blood 
draw may result in infection at the site of venipuncture. 
As with all vaccines, there is a risk of an allergic reaction or an anaphylactic event. Trial site staff 
will observe all trial subjects for at least 30 minutes after the boost vaccination. If a severe 
allergic reaction and/or dyspnoea occurs, appropriate medical treatment and supervision will be 
provided. 
As with all vaccines, there is a risk of temporary mild to moderate injection site reactions, such as 
injection site pain and/or tenderness, erythema, swelling, pruritus, or induration. The above 
mentioned were reported most commonly in the phase 1 and phase 2 studies. Also, systemic 
inflammatory reactions including flu-like symptoms such as fever, headache, nausea, muscle 
pain, chills or fatigue can occur. For further details on the safety results for the phase 1 and 
phase 2 studies, please refer to the IB. 
2.4.2 Potential Benefits 
Trial subjects will contribute significantly to the development of a vaccine targeting COVID-19 
disease. Subjects assigned to receive the ABNCoV2 vaccine might potentially acquire similar 
immunity against SARS-CoV-2 as with approved vaccines. However, it cannot be said yet 
whether ABNCoV2 vaccine is efficacious against COVID-19 disease in humans. Thus far, 
efficacy data for the ABNCoV2 vaccine are available from animal models only; human data are 
preliminary but provide support for immunogenicity of the vaccine at levels shown to confer 
protection (Gilbert et al., 2021). Subjects randomized to the active control will receive the same 
authorized Comirnaty booster vaccine that is available outside the trial. 
Analysis of the samples collected will not directly benefit the subject. Neither subjects nor their 
physicians will receive results of sample analyses. 
2.4.3 Risk/Benefit Balance 
For existing SARS-CoV-2 vaccines, the favorable risk-benefit balance is well established. Thus, 
for a new vaccine candidate such as ABNCoV2 without safety issues identified to date, the 
macro-level risk for an active controlled trial is that the vaccine may be found to be inferior to 
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approved vaccines and not provide adequate protection against COVID-19 disease, or that 
unforeseen safety concerns may arise that are greater than for approved vaccines. However, both 
preclinical and clinical data to date for ABNCoV2 suggest the vaccine induces appropriate 
measures of immunity against SARS-CoV-2 and has a favorable safety profile. The risk of 
inferiority of this candidate vaccine is balanced by the potential benefit to public health to have 
another vaccine in the armamentarium for the prevention and mitigation of COVID-19 disease.  
3 
Trial Design 
The design of the two parts of this phase 3 trial is provided below in Sections 3.1 and 3.2.  
3.1 Part A: Randomized, Double-blind, Active Controlled Component 
The randomized, double-blind, active controlled component will compare vaccination with a 
single dose of 100 g ABNCoV2 to a single 30 g adult boost dose of Comirnaty in adult 
subjects previously vaccinated for SARS-CoV-2.  
Healthy adult subjects who have previously completed vaccination with locally authorized 
SARS-CoV-2 vaccine(s) at least 3 months prior to the screening visit will be enrolled into 
2 cohorts based on the extent of prior SARS-CoV-2 vaccination: 
x 
Cohort 1: subjects who previously completed primary vaccination only 
x 
Cohort 2: subjects who have completed primary vaccination and have received 1 booster 
vaccination 
Sample size calculations are based on hypothesis testing in Part A (ABNCoV2 versus 
Comirnaty), yielding a sample size of 500 enrolled (450 evaluable) within each cohort (see 
Sections 12.2 and 12.6).  
Subjects will be randomized in a 1:1 ratio (see Section 12.1) to either ABNCoV2 or Comirnaty 
(active control arm).  
3.2 Part B: Open-label, Single-arm Component 
The open-label, single-arm component will collect safety and tolerability data from a larger trial 
population of subjects receiving ABNCoV2, as well as additional immunogenicity data from a 
subset of this population. A single 100 g dose of ABNCoV2 will be administered to up to 
3000 healthy adult subjects who have previously received their most recent locally authorized 
SARS-CoV-2 vaccination at least 3 months prior to the screening visit. These subjects will be 
enrolled into 2 cohorts: 
x 
Cohort 1 (at least 250 subjects): subjects who previously completed primary vaccination 
only 
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x 
Cohort 2 (at least 250 subjects): subjects who have completed primary vaccination and 
have received 1 booster vaccination 
Additionally, a subset of sites in the US will collect blood for serum and peripheral blood 
mononuclear cells (PBMCs) from approximately 500 subjects (200 to 250 from each cohort). 
3.3 End of Study / Study Completion 
Study completion is defined as the final date on which data are collected (i.e., the last subject’s 
last visit or scheduled assessment). 
4 Objectives 
4.1 Primary Objective 
The primary objective of this phase 3 trial is to assess the non-inferiority of vaccination with 
ABNCoV2 compared to Comirnaty in terms of neutralizing antibodies against the SARS-CoV-2 
index virus (Wuhan wild type isolate). This objective will be carried out in the randomized, 
double-blind component (Part A), in Cohort 1 (adult subjects who previously completed primary 
vaccination only) and Cohort 2 (adult subjects who have received 1 booster vaccination after a 
primary regimen) simultaneously. If the non-inferiority margin is met, superiority comparison 
will be carried out in the same cohort with the same type I error level. If for any reason, the 
minimum sample size of 400 is not met in one cohort, data from that cohort will be summarized 
descriptively.  
4.2 Secondary Objectives 
The key secondary objective is to assess the non-inferiority of vaccination with ABNCoV2 
compared to Comirnaty in terms of neutralizing antibodies against VOCs circulating at the time 
of the trial, again in Part A Cohort 1 and Cohort 2. Variants of concern might include Omicron 
(B.1.1.529), Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and/or Delta (B.1.617.2). If the non-
inferiority margin is met for a VOC, superiority comparison will be carried out in the same cohort 
with the same type I error level. 
Another secondary objective is to assess the neutralizing antibody titers against the SARS-CoV-2 
index virus in the immunogenicity subsets of the single-arm component (Part B), for Cohort 1 
and Cohort 2. 
4.3 Safety Objectives 
There are two safety objectives. The first is to compare, in the randomized, double-blind setting 
(Part A), the safety and tolerability of ABNCoV2 to Comirnaty. The second is to assess the same 
safety and tolerability endpoints among all subjects who receive ABNCoV2 (Parts A and B). 
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4.4 Exploratory Objectives 
Objectives to be explored in subsets of each Part A cohort are the following: 
x 
Vaccination with ABNCoV2 compared to Comirnaty in terms of total binding IgG 
antibodies against the SARS-CoV-2 index virus. 
x 
Kinetics of SARS-CoV-2-specific humoral responses. 
SARS-CoV-2-specific cellular responses 1 week after ABNCoV2 vaccination will be explored 
within the immunogenicity subsets of each Part B cohort. 
Another exploratory objective is to compare neutralizing antibodies against the SARS-CoV-2 
index virus at 2 weeks after vaccination with ABNCoV2 between cohorts in Part A and Part B. 
5 
Endpoints and Population-level Summaries 
5.1 Primary Endpoint 
The endpoint of subject titer of serum neutralizing antibodies against the SARS-CoV-2 index 
virus will be measured from blood samples collected 2 weeks after trial vaccination in each 
Part A cohort. The primary endpoint will be summarized as the GMTs for ABNCoV2 and 
Comirnaty. In each Part A cohort, formal hypothesis testing will be performed if a minimum of 
400 evaluable subjects has primary endpoint data available for analysis. If the sample size 
requirement is not met in one of the cohorts, formal hypothesis testing will only be performed in 
the cohort meeting the sample size requirement; results for the under-recruited cohort will be 
descriptive only. The success criterion for the null hypothesis that ABNCoV2 is inferior to 
Comirnaty will be rejected if the ratio of GMTs for ABNCoV2 versus Comirnaty is within the 
non-inferiority margin of 0.67; that is, the lower bound of the 2-sided 97.5% CI of the GMT ratio 
is 0.67. 
5.2 Secondary Endpoints 
If both Part A cohorts are tested for and meet the success criterion for the primary endpoint, 
VOCs will be tested in the cohort with the higher number of evaluable subjects, followed by the 
cohort with the smaller number of evaluable subjects if the success criterion is met in at least one 
of the tested VOCs in the cohort tested first. In the event only one cohort meets the success 
criterion for the primary endpoint, VOCs will be formally tested for the successful cohort only.  
Serum from blood samples collected for Part A at 2 weeks after trial vaccination will be analyzed 
for neutralizing antibodies against the SARS-CoV-2 VOCs (e.g., omicron, alpha to delta) 
circulating at time of the trial. Additional variants could be included in the assessment based on 
their further emergence. Those variants to be targeted for formal testing will be specified prior to 
the start of sample analysis. These key endpoints will be summarized as GMTs for ABNCoV2 
and Comirnaty. The null hypothesis of inferiority for each VOC will be rejected if the ratio of 
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GMTs against the SARS-CoV-2 VOC, for ABNCoV2 vaccine compared to Comirnaty vaccine, 
is within the non-inferiority margin of 0.67. A Bonferroni correction will be used to adjust for the 
simultaneous non-inferiority test to maintain the trial-wide type I error. 
To address the remaining secondary objective pertaining to Part B, serum from blood samples 
collected at 2 weeks after trial vaccination in the immunogenicity subset of each Part B cohort 
will be analyzed for neutralizing antibodies against the SARS-CoV-2 index virus. The endpoints 
will be summarized as GMTs for each cohort. 
5.3 Safety Endpoints 
Safety endpoints will be summarized in Part A for all subjects receiving ABNCoV2 compared to 
those receiving Comirnaty and in both parts for all subjects receiving ABNCoV2. The endpoints 
include the frequency and percentage of subjects who report the following: 
x 
SAEs or adverse events of special interest (AESIs) assessed as related to trial vaccine 
during the entire trial period, which includes both the active trial phase and follow-up. 
x 
Grade 3 or higher adverse events (AEs) assessed as related to trial vaccine in the 8-day 
period starting with the day of vaccination. 
x 
SAEs, AESIs, or medically attended AEs (MAAEs), regardless of relationship, during the 
active trial phase. 
x 
SAEs, AESIs, or MAAEs, regardless of relationship, during the entire trial period. 
x 
Grade 3 or higher AEs assessed as related to trial vaccine during the active trial phase. 
x 
Solicited local AEs in the 8-day period starting with the day of vaccination. 
x 
Solicited general AEs in the 8-day period starting with the day of vaccination. 
5.4 Exploratory Endpoints 
GMTs of total binding IgG antibody against the SARS-CoV-2 index virus will be summarized at 
baseline and post-baseline time points for ABNCoV2 and Comirnaty in subsets of each Part A 
cohort.  
Immunogenicity of ABNCoV2 and Comirnaty will be explored as the geometric mean fold 
increases from baseline to each scheduled post-baseline time points in: 
x 
Neutralizing antibodies against the SARS-CoV-2 index virus. 
x 
Neutralizing antibodies against the SARS-CoV-2 VOCs circulating at time of the trial. 
x 
Total binding IgG antibodies against the SARS-CoV-2 index virus (in subsets of each 
Part A cohort). 
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In addition, the kinetics of neutralizing antibody responses over time for ABNCoV2 and 
Comirnaty will be explored by calculating GMTs of neutralizing antibodies against the 
SARS-CoV-2 index virus and VOCs circulating at time of the trial at 1, 4, 13, and 26 weeks after 
trial vaccination in subsets of the Part A cohorts. 
Cellular immune responses at 1 week after vaccination with ABNCoV2 within the 
immunogenicity subsets of each Part B cohort will be explored by calculating the geometric 
means of SARS-CoV-2-specific T cells secreting interferon-J and interleukin-4 upon 
restimulation, as measured by ELISpot. 
6 
Study Population 
6.1 Inclusion Criteria 
Subjects must meet all the inclusion criteria listed in the Synopsis (Section 1.3) to be enrolled in 
either Part A or Part B of the trial. 
6.2 Exclusion Criteria 
The criteria that will exclude subjects from eligibility for both Parts A and B of the trial are 
provided in the Synopsis (Section 1.3). 
6.3 Inclusion of Older Subjects 
Sites will be instructed to pursue a target of 25% of enrollment to be subjects that are 65 years 
of age for Part A and 33% to be 65 years of age for Part B. The end goal is to have at least 1000 
subjects 65 years of age who receive ABNCoV2. 
6.4 Selection of Subjects 
The investigator will keep a log of subjects screened for the trial and will provide the reason in 
case of exclusion. Information about every screened subject will be documented in the electronic 
case report form (eCRF). 
For subjects who enter screening but do not proceed to vaccination, the information documented 
in the eCRF will be limited to the date of informed consent form (ICF) signature, demographics, 
and reason for screen failure, including any (S)AEs that led to the screen failure. 
6.5 Recruitment and Retention 
Subjects will be actively recruited. Recruitment strategies, including advertisements approved by 
the Independent Ethics Committee (IEC) and Institutional Review Board (IRB), will be evaluated 
by the Sponsor.  
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Individuals identified as potential subjects for the trial will be provided with all the necessary 
information required to make an informed decision about their participation. 
7 
Study Intervention 
7.1 Vaccine Dosage and Administration 
In Part A, each subject will be randomized to receive 1 dose of 100 g ABNCoV2 vaccine or 
1 adult boost dose of 30 g Comirnaty (tozinameran, BNT162b2) vaccine. An unblinded member 
of the local site team will handle the trial vaccine, while the subject and the staff involved in 
subject evaluation and follow-up will remain blinded. In case of an emergency that makes 
unblinding necessary (i.e., the subject’s safety is dependent on unblinding), a mechanism that 
permits rapid unblinding but does not permit undetectable breaks of the blinding will allow the 
Investigator the possibility of learning the treatment assignment for a subject. The detailed 
process for emergency unblinding will be described in a trial-specific procedure. 
In Part B, all subjects will receive the same single dose of 100 g ABNCoV2 as in Part A but as 
an open-label trial vaccination. All vaccinations will be administered at the investigational sites 
and injected intramuscularly into the deltoid muscle of the non-dominant arm. 
7.2 Subject Discontinuation 
A subject may be discontinued early from the active trial phase or the overall trial for different 
reasons. Reasons for early discontinuation of a subject may include, but are not limited to:  
x 
Clinical need for or receipt of concomitant or ancillary therapy not permitted in the trial as 
outlined in Section 11.4. 
x 
Subject’s receipt of an approved booster vaccination for SARS-CoV-2 outside the protocol. 
x 
Subject’s request to discontinue (withdrawal of consent to participate). 
x 
Subject unwilling or unable to comply with trial requirements.  
x 
Any reason that, in the opinion of the investigator, requires or supports early 
discontinuation of a subject. 
Each subject has the right to terminate their trial participation completely at any time for any 
reason, and the investigator may also terminate a subject’s trial participation. Subjects whose trial 
participation is terminated during the active trial phase of either Part A or Part B should undergo 
a concluding end of active phase (EAP) visit, including safety laboratory testing and pregnancy 
test for women of childbearing potential (WOCBP). The subject has the right to refuse the EAP 
visit; however, the clinical trial site (CTS) should make every effort to collect any safety data 
possible for the subject. If the subject is willing, the 2-month follow-up (FU) phone call (FU1), 
the 3-month FU visit (FU2), and/or the 6-month visit (FU3) should still be performed to collect 
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any potential SAEs/AESIs which occurred after vaccination. Subjects who discontinue after 
receiving trial vaccine will not be replaced. 
8 
Schedule of Procedures by Visit 
The trial procedures will be conducted according to the trial procedure schedule (Section 1.4) and 
as described on the following pages. Visits must be scheduled within the protocol-allowed visit 
windows. 
8.1 Screening Visit 
All subjects must be thoroughly informed about all aspects of the trial (e.g., trial visit schedule, 
required evaluations and procedures, risks and benefits) as described in the ICF. Written 
informed consent must be obtained according to local requirements before any trial-related 
assessments may be carried out. 
After the written informed consent has been obtained, subjects will enter a screening period of up 
to 14 days before the trial vaccination. Screening procedures are listed in the trial procedure 
schedule in Section 1.4. 
If a subject has been screened and cannot be vaccinated because of a certain transient condition 
(e.g., abnormal lab value due to an acute condition or a missing lab evaluation due to mishandling 
of the sample), the respective test(s) should be repeated. The re-test must be performed, and 
eligibility determined within the 14-day window started by the initial screening visit.  
If a subject cannot be vaccinated due to other circumstances (e.g., completion of a wash-out 
period for a medication or vaccine not allowed during the trial) leading to a delay over the 14-day 
window, a complete re-screening must be performed, and a new subject number will be assigned. 
The clock then re-starts at the new screening visit within 14 days before randomization. A subject 
may be fully re-screened only once. 
8.2 Active Phase 
8.2.1 Visit 1 
After successfully passing the screening evaluations, the eligible subjects for Part A can be 
randomized and vaccinated with ABNCoV2 or Comirnaty, no later than 14 days after the start of 
screening. Eligible volunteers for Part B can be vaccinated with ABNCoV2, again no later than 
14 days after the start of screening. The procedures performed at Visit 1 are listed in the trial 
schedule in Section 1.4. With respect to timing, procedures listed above the randomization event 
in the trial schedule should be performed prior to randomization and vaccination; of greatest 
importance is that collection of samples for serum antibody titers, PBMC testing, and 
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nucleocapsid protein antibody testing must always be performed prior to vaccine administration. 
Refer to Section 12.1 for randomization procedures.  
Investigational sites will be provided with instructions for administration of trial vaccine. 
Subjects will be observed for 30 minutes after vaccine administration, and AEs that occur 
immediately following trial vaccination will be collected. The site coordinator also will give the 
memory aid (along with appropriate instruction) to subjects at Visit 1 for them to record any 
solicited AEs that occur after vaccination, for a period of 8 days (the day of vaccination and the 
next 7 days). 
8.2.2 Visit 2 
Visit 2 is to occur 5 to 7 days after trial vaccination. The procedures performed at Visit 2 are 
listed in the trial schedule in Section 1.4. Core procedures performed in the active phase visits 
following trial vaccination include the evaluation of vital signs, recording of concomitant 
medications, targeted physical examination, and AE recording. Blood samples are collected for 
serum antibody titers from subjects in Part A and for PBMCs from subjects in the Part B 
immunogenicity subset.  
Subjects are asked if they have any SARS-CoV-2 symptoms or tested positive between Visit 1 
and Visit 2, and if so, responses will be recorded as AEs. A SARS-CoV-2 infection polymerase 
chain reaction (PCR) test may be performed if it is determined to be clinically indicated. 
As Visit 2 is the first visit following trial vaccination, site personnel are to examine the injection 
site and review the memory aid with the subject. Expected injection site reactions are to be 
recorded by the subject with solicited AEs on the memory aid. Unexpected findings are to be 
recorded by site personnel as AEs. All completed pages of the memory card are collected. If there 
are any symptoms that have not yet resolved the site should counsel the subject regarding 
continued collection of symptoms using the memory aid. 
8.2.3 Visit 3 
Visit 3 is to occur 2 weeks after trial vaccination, ±2 days. The procedures performed at this visit 
are listed in the trial procedure schedule in Section 1.4. In addition to the core set of trial 
procedures listed above, a blood draw is performed at this visit for safety labs in all subjects, and 
for serum antibody titers and nucleocapsid protein antibody testing in Part A and in the Part B 
immunogenicity subset. The subjects are asked if they have any SARS-CoV-2 symptoms or 
tested positive since the last visit. If there were any unresolved solicited symptoms at the prior 
visit, the memory aid is reviewed with the subject and all completed pages collected.  
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8.2.4 Visit 4 / End of Active Phase
Visit 4 is the last visit in the active phase of both parts of the trial, and it occurs 4 to 5 weeks after 
trial vaccination. As shown in Section 1.4, the core trial procedures are performed at this visit, a
final pregnancy test is done for WOCBP, and blood is collected for serum antibody titers in 
Part A. The subjects are asked if they have any SARS-CoV-2 symptoms or tested positive since 
the last visit. If there were any unresolved solicited symptoms at the prior visit, the memory aid is 
reviewed with the subject and all completed pages collected.
8.3
Follow-up Phase
To monitor safety and immunogenicity, all subjects will receive 1 phone call at 2 months (FU1, 
days 56 to 70) and attend 2 visits, at 3 months (FU2, days 91 to 105) and 6 months (FU3,
days 182 to 196) after trial vaccination. The phone call involves collection of AESIs and SAEs 
only. For the follow-up visits, as shown in the trial schedule in Section 1.4, the core procedures 
from the active phase are repeated, including collection of MAAEs, AESIs, and SAEs, but
concomitant medications and other AEs are no longer recorded, and blood collection for serum 
antibody and nucleocapsid protein testing occurs only in Part A. The subjects are asked if they 
have any SARS-CoV-2 symptoms or tested positive since the last visit. The memory aid may be 
collected at the FU2 visit if not collected previously and all symptoms have resolved. At the FU3 
visit, the memory aid will be collected regardless of ongoing symptoms for recording.
8.4
Unscheduled Visit
Clinically indicated additional procedures or visits may be necessary at any time, including 
between scheduled visits. Unscheduled visits may be performed, e.g., to repeat laboratory testing 
or physical exams due to a new development, to do PCR testing for suspected COVID-19
infection, or to perform any clinically indicated evaluation, such as an electrocardiogram (ECG).
Examinations performed at unscheduled visits will be recorded in the source documents as well 
as in the respective eCRF sections for unscheduled visits.
9
Investigational Medicinal Product
9.1
Production, Packaging and Labeling
ABNCoV2 drug product is released by Bavarian Nordic A/S, DK. 
Address:
Bavarian Nordic A/S
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The packages and vials of ABNCoV2 vaccine are labeled according to regulatory requirements. 
Vials contain at least 100 g in 0.5 mL.  
Comirnaty is a commercially available product and will not be relabeled for trial purposes. For 
further details, please refer to the prescribing information for Europe and the US: 
x https://www.ema.europa.eu/en/documents/product-information/comirnaty-epar-product-
information_en.pdf 
x https://www.fda.gov/media/151707/download 
9.2 Shipment, Storage and Handling 
Usage of the investigational medicinal product (IMP) is only allowed upon final approval of all 
shipment relevant paperwork by Bavarian Nordic (BN) or its authorized designee. Only subjects 
enrolled in the trial may receive IMP. 
ABNCoV2 and Comirnaty vaccine will be temperature controlled and monitored during shipment 
to the CTS. Once at the site, the package should be handed over to the personnel in charge of 
IMP preparation (e.g., the pharmacist). Site personnel are responsible for proper storage of IMP 
upon receipt. All IMP must be stored in a secure, environmentally controlled and monitored area 
in accordance with the required storage conditions, with access limited to the investigator and 
authorized site staff. 
ABNCoV2 vaccine is shipped and stored at -20°C (±5°C). Comirnaty vaccine is shipped and 
stored according to package leaflet instructions. For further details see the pharmacy manual. 
9.3 Preparation 
The preparation of trial vaccine will be performed by authorized personnel only. An unblinded 
member of the local site team will handle the trial vaccine, while the subject and the staff 
involved in subject evaluation and follow-up will remain blinded. Trial-specific details on 
preparation of the ABNCoV2 and Comirnaty vaccines are provided in the pharmacy manual. 
9.4 Accountability and Disposal 
Used (if allowed by institutional policy) and unused vials of all IMP need to be retained in a 
place with limited access until appropriate drug accountability has been performed. Drug 
accountability must be documented whenever the IMP is either prepared or administered.  
BN will provide a Drug Accountability Log for recording receipt, dispensation, and destruction 
of IMPs (see separate pharmacy manual). Alternative systems used to track drug accountability 
are acceptable for use in the trial provided the aforementioned items are adequately captured and 
records are available for review during scheduled monitoring visits to the site.  
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After drug accountability has been performed, used and unused vials should either be returned to 
the designated drug depot, a vendor selected by BN or discarded according to local regulations.
Destruction or return of IMP must be agreed upon with BN and appropriately documented. 
Documentation should be reviewed and signed off by the pharmacist and Clinical Research 
Associate (CRA) assigned to monitor the site. 
Sites are responsible for the proper destruction and disposal of used needles and syringes, which
should be performed according to local regulations. If local disposal is not possible, used clinical 
supplies may be returned to BN or to the designated drug depot after prior consultation with BN.
10 Assessment of Immunogenicity
The immunogenicity of ABNCoV2 and Comirnaty will be assessed by measuring humoral 
responses on serum samples collected from all subjects in Part A and from an immunogenicity
subset of subjects in Part B.
Immunogenicity testing will be performed at 
and 
at contracted laboratories, where applicable. Testing will be conducted according to applicable
standard operating procedures (SOPs) that are in effect at the time of testing. A list of applicable
SOPs in effect will be included in the electronic Trial Master File.
The procedures for collection, preparation, storage and shipment of specimens for 
immunogenicity testing (serum and PBMC) are specified in lab manuals/study-specific 
instructions, which will be provided to the investigators/CTS personnel as well as to the 
processing laboratories before recruitment commences. Additionally, investigators and CTS staff 
will be trained in the procedures during the investigator meeting/site initiation visit.
10.1 Humoral Immune Response
As outlined in Section 1.4, serum samples for Part A will be collected from subjects at all active 
trial phase and in-person follow-up visits, and for the Part B immunogenicity subset, enrolled at 
select investigational sites, at baseline (Visit 1) and Visit 3. In both parts, samples for 
immunogenicity testing obtained at Visit 1 will be drawn prior to vaccination.
SARS-CoV-2-specific antibody responses will be assessed in trial subjects using neutralization 
tests (e.g., pseudo virion assay; neutralizing antibodies) and enzyme-linked immunosorbent assay 
(ELISA; total antibodies)
10.2 Cellular Immune Response
PBMC samples will be collected as outlined in the trial procedure schedule in Section 1.4 (at 
Visits 1 and 2) at selected investigational sites participating in the Part B immunogenicity subset.
Samples for immunogenicity testing obtained at Visit 1 will be drawn prior to vaccination.
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SARS-CoV-2-specific T-cell responses, e.g., SARS-CoV-2-specific T cells secreting 
interferon-J / interleukin-4 upon restimulation, will be assessed using enzyme-linked immuno 
spot technique (ELISpot).
10.3 Nucleocapsid Protein Antibody Testing
Serum samples also will be used to analyze nucleocapsid protein antibody titers as outlined in the 
trial procedure schedule in Section 1.4 at Visits 1 and 3 and Follow-up 2 and 3 in Part A and at 
Visits 1 and 3 at selected investigational sites participating in the Part B immunogenicity subset. 
Samples for nucleocapsid protein antibody testing obtained at Visit 1 will be drawn prior to 
vaccination.
10.4 Future Use of Lab Specimens
Specimens remaining after completion of immunogenicity testing as per protocol might be stored 
for possible future research and analysis supporting the licensure path of ABNCoV2 vaccines. 
Future testing will facilitate the bridging of trial results to animal immunogenicity results and/or 
to immune response data collected from subjects vaccinated with other COVID-19 vaccines. 
Further, remaining samples might be used for assay development and controls. Subjects will be 
invited to consent to storage/future use of their samples and will be informed about data 
protection measures. Specimens will be stored in BN’s secured laboratory area in 
 
or at an external storage facility in a coded, pseudonymized manner to ensure data 
protection. Genetic testing will not be performed.
11 Safety and Reactogenicity
Safety will be monitored in both Part A and Part B by collection of medical history and 
performance of an electrocardiogram (ECG) at baseline, physical examination including vital 
signs at in-person visits, and routine laboratory measurements (including pregnancy testing and 
counseling on avoidance of pregnancy for WOCBP). Local and general solicited AEs and 
unsolicited AEs will be recorded. AESIs are defined as per Section 11.9 and are reported 
following the same workflow as SAEs, with the exception that AESI collection begins after 
receipt of vaccination.
11.1 Definitions
11.1.1 Medical History
Symptoms, relevant laboratory findings and ongoing medical conditions present before and/or at 
screening will be documented as medical history.
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11.1.2 Adverse Events  
Adverse events are defined by the International Council for Harmonisation (ICH) E6(R2) as any 
untoward medical occurrence in a subject administered a medical product, regardless of whether 
there is a causal relationship associated with the administration of the IMP. For this study, any 
new signs, symptoms, laboratory findings or changes in health starting after informed consent are 
documented in the subjects’ records and the AE section of the eCRF. Adverse events are 
recorded based on unsolicited and solicited questioning (Sections 11.1.3 and 11.1.4).  
11.1.3 Unsolicited AEs 
Unsolicited AEs are defined as AEs which are not pre-listed on the memory aid. Adverse events 
(e.g., feeling of ill-health, subjective symptoms and objective signs, intercurrent diseases, 
accidents, etc.) observed by the investigator and/or reported by the subject must be recorded in 
the eCRF regardless of the assessment of causality in relationship with the IMP/MP. 
After vaccination, abnormal laboratory findings assessed as being clinically significant by the 
investigator are to be documented as AEs. In addition, after vaccination abnormal laboratory 
findings fulfilling the Grade 3 or Grade 4 criteria according to the toxicity scale (Appendix 1) are 
to be documented as AEs in the eCRF, regardless of whether they are considered clinically 
relevant. For lab values fulfilling the Grade 3 or Grade 4 criteria, the decision to repeat the labs is 
left to the discretion of the principal investigator (PI). Toxicity grade and seriousness of an AE 
will be assessed separately, i.e., a Grade 3 or Grade 4 AE will not automatically be regarded as 
serious. 
The investigator should ask the subjects at each visit if they have experienced any AEs since their 
last visit. All intercurrent diseases reported by the subject need to be recorded by the investigator 
in the appropriate section of the eCRF. 
11.1.4 Solicited AEs 
In this clinical trial protocol, solicited AEs are defined as all symptoms specifically listed in the 
memory aid provided to the subjects following vaccination. After vaccination, the subjects are 
requested to monitor and record local symptoms (i.e., erythema, swelling, induration, pruritus and 
pain at the injection site) as well as general symptoms (i.e., body temperature increase or pyrexia, 
headache, chills, myalgia, nausea and fatigue) in the memory aid daily for the day of vaccination 
and the following 7 days (an 8-day period). Any symptoms that persist at the end of this period 
will continue to be measured and documented each day until resolved. 
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11.1.5 Serious Adverse Events, Serious Adverse Reactions, Adverse Events of Special 
Interest, and Medically Attended Adverse Events 
An SAE is any untoward medical occurrence or effect in a subject administered the trial vaccine 
that may or may not have a causal relationship with the study vaccine and that is serious, 
meaning that it: 
x Results in death; 
x Is life-threatening; 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death, if it were more severe. 
x Requires in-patient hospitalization or prolongation of existing hospitalization; 
x Results in persistent or significant disability or incapacity; 
x Results in a congenital anomaly or birth defect; or 
x Is an otherwise important medical event, e.g., leads to suspicion of transmission of an 
infectious agent. 
Though SAEs, as specified above, include all serious events independent of whether they have a 
suspected causal relationship to the IMP or not, serious adverse reactions (SARs) are defined as a 
subset of SAEs that include all noxious and unintended responses to the IMP related to any dose 
administered that at any dose results in any of the serious outcomes listed above. 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 subject 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; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
AESIs are generally defined as AEs that meet the following criteria: 
x 
Known association with immunization or a specific vaccine platform; 
x 
Theoretical association based on animal models; 
x 
Occurrence during wild type disease as a result of viral replication and/or 
immunopathogenesis. 
AESIs for this trial are defined as per Section 11.9. 
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All AEs are collected from signing of ICF but should not be considered by the investigator to be 
an AESI unless occurring since receipt of trial vaccination.  
MAAEs are defined as adverse events with medically attended visits that were not routine visits 
for physical examination or vaccination, such as visits for hospitalization, an emergency room 
visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any 
reason. 
11.2 Relevant Medical History 
Relevant medical history will be self-reported and documented at screening and will focus 
particularly on any important diseases and in the case of infections or tumors, the pathogen 
involved or the pathological diagnosis, if available. In particular, for subjects with prior 
COVID-19 infection, the infection and dates must be included in the eCRF. Additionally, 
laboratory reports need to be documented during screening. All ongoing conditions for which the 
subjects are taking medications, and/or which may exacerbate during the trial period should be 
considered as important. Special attention should be given to history of prior allergic reactions, 
especially to vaccines.  
11.3 Prior and Concomitant Medication 
All concomitant (ongoing) medication except homeopathic substances and dietary supplements 
must be recorded in the subject’s medical record and in the eCRF including information about the 
indication, dosage regimen, and the onset and end of treatment. 
The following medications taken within 3 months prior to screening will also be recorded in the 
eCRF and the subject’s medical record: vaccines (e.g., influenza/pneumococcal), corticosteroids 
(via any route of administration), other immune-modulating drugs, immunoglobulin and/or any 
blood products, investigational drugs, and depot preparations that are still active at the date of 
screening. In addition, previous SARS-CoV-2 vaccination record will include the specific 
vaccine received with dose and date(s) in the eCRF, regardless of the time elapsed prior to 
screening. 
11.4 Prohibited Medications 
Prohibited medication or medication where washout periods need to be adhered to are (see also 
eligibility criteria in the Synopsis [Section 1.3]): 
x 
Administration of any SARS-CoV-2 vaccine other than the trial vaccine for the entire trial 
period. 
x 
Vaccination with any licensed live vaccine within 30 days prior to or after trial vaccination 
or any licensed non-live vaccine within 14 days prior to or after trial vaccination. 
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x 
Chronic systemic administration (defined as more than 14 days) of >5 mg prednisone (or 
equivalent) per day or any other systemic use of immune-modifying drugs during a period 
starting 3 months prior to administration of the trial vaccine and ending at the last visit of 
the active trial phase. The use of topical, inhaled, ophthalmic and nasal corticoids will be 
permitted. 
x 
Administration of immunoglobulins and/or any blood products during a period starting 
3 months prior to administration of the trial vaccine and ending at the last visit of the active 
trial phase. 
x 
Use of any investigational or non-registered drug or vaccine other than the trial vaccine 
within 30 days preceding the administration of the trial vaccine, or planned administration 
of such a drug or vaccine during the entire trial period (i.e., through 6 months after the trial 
vaccination). 
11.5 Physical Examination 
11.5.1 Complete Physical Examination 
A complete physical examination (excluding breast, genital, and rectal examinations) will be 
performed at screening. The examination includes a review of major organ systems as well as 
body height and weight. The examination should be directed at finding evidence of any 
infections, tumors and lymphadenopathy (a grading scale for lymphadenopathy is included in 
Appendix 2). In addition, auscultation of the heart and lungs will be performed to check 
specifically for signs of any heart condition or respiratory disorders. 
Any clinically significant findings at the screening physical examination will be recorded as 
medical history events. The only data captured in the eCRF for the physical examination itself 
will be the date it was performed. Any new or worsening clinically significant findings 
post-treatment will be captured as AEs.  
11.5.2 Targeted Physical Examination 
A targeted physical examination, guided by any signs or symptoms previously identified or any 
new symptoms that the subject has experienced since the last visit, is required according to the 
trial schedule (Section 1.4). In addition, auscultation of the heart and lungs will be performed to 
check specifically for signs of any heart condition. 
Any new or worsening of clinically significant findings from the active trial phase physical 
examinations will be recorded as AEs. 
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11.6 Vital Signs 
At screening and every other in-person trial visit as defined in the trial schedule (Section 1.4), 
blood pressure and pulse rate will be taken after the subject has been sitting upright for 
approximately 2 minutes. Body temperature will be measured orally. 
11.7 Unsolicited AEs 
All intercurrent diseases reported when the investigator actively questions the subject will be 
documented and all required details (e.g., start and stop date, intensity) will be assessed. 
Unsolicited AEs will be reported in the subject’s medical record and respective section of the 
eCRF (for requirements for screen failures, see Section 15.1).  
Unsolicited AEs will be assessed and documented from ICF signature through EAP, and if 
ongoing at that time, followed until resolution or until the subject’s last trial visit, at the latest. 
SAEs, AESIs, and MAAEs will be collected throughout the entire trial, including during the FU 
period. 
(S)AEs would only be considered as AESIs once subject has received the trial vaccination. SAEs 
and AESIs will be followed-up until resolution or achievement of stable clinical conditions. 
Assessment of Intensity  
For all unsolicited AEs not represented in the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA, 2007), the 
maximum intensity will be based on the following descriptions: 
Grade 1 
An AE which is easily tolerated by the subject, causing minimal discomfort and 
not interfering with daily activities. 
Grade 2 
An AE which is sufficiently discomforting to interfere with daily activities, but 
does not require medical intervention (non-narcotic pain reliever or other 
nonprescription medication are not considered “medical intervention” for this 
purpose). 
Grade 3 
An AE which prevents daily activities, and which requires medical intervention 
(non-narcotic pain reliever or other nonprescription medication are not considered 
“medical intervention” for this purpose). 
Grade 4 
Life-threatening, or disabling. 
Assessment of Causality  
The relationship between the occurrence of an AE and the IMP will be assessed using the 
categories presented below. For expedited reporting and all other purposes, the categories “not 
related” and “unlikely” will represent no evidence or argument to suggest a causal relationship, 
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while “possible”, “probable” and “definite” will be seen to convey that there is evidence or 
argument to suggest a causal relationship. To ensure reporting, all AEs without a causality 
assessment from the investigator will preliminarily be classified as “possible”. 
In terms of binary causality assessments unlikely and not related in clinical trials is lumped to 
“not related” whereas other causality assessments as per below are lumped to “related”.  
Not 
related 
The time interval between administration of the IMP and the occurrence or 
worsening of the AE rules out a relationship, and/or alternative cause is established 
and there is no evidence of a (concomitant) causal connection with or worsening 
caused by the IMP. 
Unlikely 
The time interval between administration of the IMP and the occurrence or 
worsening of the AE makes a causal relationship unlikely, and/or the known effects 
of the IMP or substance class provide no indication of a (concomitant) causal 
connection with or worsening caused by the IMP and there is another cause which 
serves as an adequate explanation, and/or although the known effects of the IMP or 
substance class make it possible to derive a plausible causal chain with regard to a 
(concomitant) causal connection or worsening, however, another cause is 
considerably more likely, and/or another cause of the AE has been identified and a 
(concomitant) causal connection with or worsening caused by the IMP is unlikely. 
Possible 
A plausible causal chain regarding a (concomitant) causal connection with / 
worsening of the AE can be derived from the pharmacological properties of the IMP 
or substance class. However, other approximately equally likely causes are known, 
or although the pharmacological properties of the IMP or substance class provide no 
indication of a (concomitant) causal connection with / worsening of the AE, there is 
no other known cause which provides an adequate explanation. 
Probable 
The pharmacological properties of the IMP or substance class, and/or the course of 
the AE after discontinuation of the IMP and possible subsequent re-exposure, and/or 
specific findings (e.g., positive allergy test or antibodies against the IMP / 
metabolites) suggest a (concomitant) causal connection with / worsening of the AE 
resulting from the IMP, however another cause cannot completely be ruled out. 
Definite 
The pharmacological properties of the IMP or substance class and/or the course of 
the AE after discontinuation of the IMP and possible subsequent re-exposure, and/or 
specific findings (e.g., positive allergy test or antibodies against the IMP / 
metabolites) definitely indicate that there is a (concomitant) causal connection with / 
worsening of the AE resulting from the IMP and there are no indications of other 
causes. 
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11.8 Solicited AEs 
After the vaccination, subjects receive a memory aid to record solicited local and general AEs 
most likely to occur on the day of vaccination and the following 7 days (Days 1 to 8). 
All solicited symptoms observed after vaccination with details concerning the intensity and the 
course of the symptom should be documented in the memory aid. The CTS will review the 
memory aid with the subject, and when it is completed (all symptoms have resolved), will 
transfer the results to the eCRF and the subject’s medical record. The investigator’s assessment of 
the symptoms will also be recorded in the eCRF including causality (for solicited general AEs), 
seriousness, outcome, and any intervention required. Local and general symptoms still ongoing 
after 8 days will continue to be measured and documented each day until resolved on the memory 
aid. 
To standardize procedures uniform rulers will be handed out to subjects for measurements of 
erythema, swelling and induration diameters, as will digital thermometers for oral measurements 
of body temperature.  
In case of severe and unexpected local and/or general reactions, the subject should be instructed 
to contact the trial physician outside of scheduled trial visits. 
11.8.1 Solicited Local AEs  
The solicited local symptoms erythema, swelling, induration, pruritus and pain at the injection 
site are to be documented in the memory aid by the subjects. 
Assessment of Intensity 
Injection site erythema, swelling, and induration will be assessed based on the longest diameter 
as measured by the subject in mm and recorded in the memory aid. Subjects are asked to 
document the solicited local AEs in the memory aid. For injection site erythema, injection site 
swelling, and injection site induration, subjects are asked to record longest diameters; for 
injection site pruritus and injection site pain, subjects are asked to record level of severity as 
described in Table 2 below. 
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Table 2 
Grading of Local Symptoms from the Subject’s Memory Aid 
MedDRA coded Preferred Term 
Local Adverse Events 
Grading for Analyses 
Grading Assessed at Diary 
Review 
Grade 
Severity Measurea 
Grade 
Severity Measure 
Injection site erythema, Injection 
site swelling, and Injection site 
indurationb (longest diameter) 
0 
0 cm 
0 
0 mm 
1 
2.5 – 5 cm 
1 
<30 mm 
2 
5.1 – 10 cm 
2 
30 – <100 mm 
3 
>10 cm 
3 
100 mm 
Injection site pruritus 
 
Same as assessed at 
diary review 
0 
Absent 
1 
Mild 
2 
Moderate 
3 
Severe 
Injection site pain 
 
Same as assessed at 
diary review 
0 
Absent 
1 
Painful on touch 
2 
Painful when limb 
is moved 
3 
Spontaneously 
painful/prevents 
normal activity 
a Per FDA “Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials”, September 2007. Available at 
https://www.fda.gov/media/73679/download. 
b Per FDA guidance, injection site swelling and induration are combined (i.e., injection site swelling/induration). 
Assessment of Causality  
Solicited local AEs are defined as being related to the vaccine. 
11.8.2 Solicited General AEs 
The solicited general symptoms body temperature, headache, myalgia, nausea, chills and fatigue 
are to be documented in the memory aid by the subjects. 
Assessment of Intensity  
Subjects are asked to document the solicited general AEs in the memory aid. Subjects are asked 
to record temperature and severity of symptoms as described in Table 3 below. In the subject’s 
memory aid, the grading of symptom intensity is described in basic, easily understood language 
based on the following descriptions: 
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Table 3 
Grading of General Symptoms from the Subject’s Memory Aid 
MedDRA coded Preferred Term 
General Adverse Events 
Grading for Analyses 
Grading Assessed at Diary 
Review 
Grade 
Severity Measurea 
Grade 
Severity Measure 
Body temperature (oral)b 
0 
<38.0°C (<100.4°F) 
0 
<37.5°C (<99.5°F) 
1 
38.0 – 38.4°C 
(100.4 – 101.1°F) 
1 
37.5 – <38.0°C 
(99.5 – <100.4°F) 
2 
38.5 – 38.9°C 
(101.2 – 102.0°F) 
2 
38.0 – <39.0°C 
(100.4 – <102.2°F)  
3 
39.0 - 40°C 
(102.1 – 104°F) 
3 
39.0 – <40.0°C 
(102.2 – <104.0°F) 
4 
>40°C (>104°F) 
4 
40.0°C (104.0°F)  
Headache, Myalgia, Nausea, Chills 
and Fatigue 
 
Same as assessed at 
diary review 
0 
None 
1 
Mild: easily 
tolerated, minimal 
discomfort and no 
interference with 
daily activity 
2 
Moderate: Some 
interference with 
daily activity 
3 
Severe: Prevents 
daily activity 
a Per FDA “Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials”, September 2007. Available at 
https://www.fda.gov/media/73679/download. 
b Pyrexia is defined as oral temperature 38.0°C (100.4°F), which is fever Grade 1 by FDA grading and oral 
temperature Grade 2 as assessed at diary review. 
Assessment of Causality  
Causal relationship between solicited general AEs and the vaccine will be assessed by the 
investigator using the same categories as for unsolicited AEs (see Section 11.7). 
11.9 Adverse Events of Special Interest 
11.9.1 General AESI Definitions 
For this trial, AESIs are defined according to the following lists of AESIs available: 
1. 
Brighton Collaboration SPEAC – Safety Platform for Emergency vACcines (SPEAC) 
Project generated list of AESI for safety monitoring (accessible via 
https://brightoncollaboration.us/covid-19/). This list is updated on a quarterly basis and the 
current effective list of AESIs is applicable for this trial. Links to the Brighton 
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Collaboration’s case definitions for AESIs applicable for COVID-19 vaccine trials are 
provided in Appendix 3. 
2. 
ACCESS Project List of Adverse events of special interest and case definitions (accessible 
via http://www.encepp.eu/documents/DraftReport.pdf). 
3. 
CBER Surveillance Program – List of Adverse Events of Special Interest (accessible via 
https://www.bestinitiative.org/wp-content/uploads/2021/02/C19-Vaccine-Safety-AESI-
Background-Rate-Protocol-FINAL-2020.pdf). 
4. 
Additionally, confirmed COVID-19 infection is also considered as AESI. Confirmed 
COVID-19 infection requires laboratory confirmation of SARS-CoV-2 using reverse 
transcription PCR methods (ECDC, 2020).  
BN has compiled an all-inclusive list of AESIs based on references provided above, which is part 
of investigator training materials.  
For timelines for reporting and follow-up of AESIs, see Section 11.14.1. The same timelines and 
reporting processes as for SAEs are applicable. 
11.9.2 Myocarditis and Pericarditis 
Myocarditis and pericarditis are a subset of AESIs of particular interest. Postmarketing data from 
mRNA vaccine recipients have demonstrated increased risks of myocarditis and pericarditis in 
males under the age of 40 years following a second dose of mRNA vaccine. Cases have been 
reported in older males and in females as well, and also following other doses. Available data 
from short-term follow-up suggest that most individuals have had resolution of symptoms with 
conservative management, although information is not yet available about potential long-term 
sequelae. 
The spike (S) protein antigen can induce antibodies to SARS-CoV-2 spike glycoproteins that 
cross-react with myocardial contractile proteins, including myocardial Į-myosin heavy chain 
(Vojdani and Kharrazian, 2020). In contrast to the currently licensed COVID-19 vaccines, the 
ABNCoV2 candidate vaccine does not contain the full-length S protein of the SARS-CoV-2 
virus, but specifically the receptor binding domain (RBD) of the S protein. However, as the 
pathomechanism for myocarditis or pericarditis following COVID-19 vaccination is not fully 
understood, and the specific role of the RBD remains unclear, precautionary measures will be 
implemented for this trial. 
Symptoms of myocarditis or pericarditis include chest pain, shortness of breath, or feelings of 
having a fast-beating, fluttering, or pounding heart, with onset of symptoms most commonly 
reported within a few days following vaccination. While some cases required intensive care 
support, available data from short-term follow-up suggest that symptoms resolve in most 
individuals with conservative management. Information is not yet available about potential long-
term sequelae. Subjects will receive educational materials explaining the symptoms of 
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myocarditis and pericarditis and instructing them to seeking medical attention if they occur. 
Subjects reporting acute chest pain, shortness of breath, palpitations, or other signs or symptoms 
of myocarditis or pericarditis within 4 to 6 weeks after vaccination will be referred to a 
cardiologist for evaluation and management. Cases of myocarditis and pericarditis will be 
followed until resolution of symptoms and abnormal test findings. 
Determination of myocarditis and pericarditis will be performed based on the case definitions and 
guidelines from the Brighton Collaboration Myocarditis/Pericarditis Working Group (Sexson 
Tejtel et al., 2022). Reference to the publication of these case definitions is provided in Appendix 
3. Cases of myocarditis or pericarditis occurring in temporal association with vaccination will be 
considered as potentially related, unexpected, and serious (as important medical events, even if 
other seriousness criteria are not met). These will be included in expedited reporting for the trial. 
An adverse event follow-up questionnaire for cardiac events (Appendix 4) will be used during the 
study. 
The DMC will review cases of myocarditis and pericarditis, with details as to the timelines for 
review and ad-hoc meetings to be described in the DMC charter (Section 13.3.1). In addition, 
recommendations for pausing or halting the trial will be in line with the stopping rules described 
in Section 13.3.2. 
11.10 Confirmed COVID-19 Infection with Severe Manifestations or Resulting in 
Critical Illness 
All cases of COVID-19 disease with severe manifestations or resulting in critical illness will be 
reviewed periodically by the DMC. 
Severe COVID-19 in adults is defined as dyspnea, a respiratory rate of 30 or more breaths per 
minute, a blood oxygen saturation of 93% or less, a ratio of the partial pressure of arterial oxygen 
to the fraction of inspired oxygen (Pao2:Fio2) of less than 300 mm Hg, or infiltrates in more than 
50% of the lung field (Berlin et al., 2020). Critical illness is defined as respiratory failure, septic 
shock, and/or multiple organ dysfunction (NIH, 2021). 
11.11 Safety Laboratory Measurements 
The intensity of laboratory/systemic toxicities measured quantitatively will be graded according 
to the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials (FDA, 2007). The laboratory values provided in this toxicity 
grading scale serve as guidelines and are dependent upon institutional parameters. Institutional 
specific toxicity gradings will be included in site specific manuals as needed. 
Safety laboratory measurements are obtained at Screening and Visit 3 and at any other visit(s) if 
clinically indicated. For subjects who discontinued during the trial and are coming for the EAP 
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visit so that final safety data can be collected, safety labs may be done at this time. Safety 
laboratory parameters to be evaluated are: 
Hematology: 
Red blood cell count, hemoglobin, total and differential white blood cell count (WBC), platelet 
count, hematocrit, mean corpuscular/cell volume (MCV), mean corpuscular/cellular hemoglobin 
(MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell distribution 
width (RDW) are routinely performed as part of the complete blood cell count and will be 
included in the laboratory report. 
Serum chemistry: 
Total bilirubin, ALP, AST, ALT, serum creatinine, sodium, potassium, calcium, c-reactive 
protein. 
Pregnancy test: 
A ȕ-human choriogonadotropin (ȕ-HCG) pregnancy test will be conducted for all WOCBP at 
screening, prior to vaccination, and at EAP. At screening a serum ȕ-HCG pregnancy test will be 
performed; other pregnancy tests will be conducted as urine ȕ-HCG tests. 
Virology:  
The following parameters will only be evaluated during the screening period for assessment of 
inclusion/exclusion criteria: 
x Human immunodeficiency virus antibody (anti-HIV) 
x Hepatitis B surface antigen (HbsAG) 
x Hepatitis C antigen (HCV) 
SARS-CoV-2 Testing: 
Testing by PCR for SARS-CoV-2 infection will be done at screening. It also will be performed at 
any time throughout the trial starting after vaccination if clinically indicated (e.g., in the presence 
of typical COVID-19 symptoms; see the trial schedule, Section 1.4). 
Positive SARS-CoV-2 infections, whether detected by testing within the trial or outside the trial, 
should be reported as AESIs (see Section 11.10). 
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11.12 Cardiac Assessment
A standard 12-lead ECG will be required at screening. An ECG may be performed at any other 
visit if clinically indicated. The investigator will assess the clinical significance for abnormal
ECGs.
11.13 Pregnancy
As per inclusion criteria, WOCBP must have a negative serum pregnancy test at screening and a 
negative urine pregnancy test at randomization. In addition, WOCBP and male subjects who are 
sexually active with WOCBP must have used an acceptable method of contraception for 30 days 
prior to the trial vaccination, must agree to use an acceptable method of contraception during the 
trial, and must avoid pregnancy for at least 30 days after the vaccination. Nevertheless, 
IMP-exposed pregnancies cannot be excluded with certainty. Subjects who become pregnant 
prior to vaccination will be excluded from the trial and are regarded as screening failure. Subjects 
who become pregnant during the active trial phase (up to and including 1 month [minimum 
28 days] after receiving trial vaccine) may continue trial procedures at the discretion of the 
investigator. All reports, where the embryo or fetus may have been exposed to the IMP will be 
followed-up until delivery to collect information on the outcome of the pregnancy (see 
Section 11.14.3).
Subjects will be instructed to notify the investigator if it is determined (also after completion of 
the trial) that they became pregnant during the trial.
11.14 Reporting
11.14.1 Reporting of SAEs and AESIs
All SAEs (collection starts at signing of ICF) and AESIs (collection starts upon vaccination)
occurring throughout the entire course of the trial, to include the active trial and follow-up period,
must be entered in the eCRF within 24 hours of awareness by the investigators, which triggers an 
autogenerated output to the drug safety department of
, the contract research organization 
(CRO) for this trial.
In case the eCRF is unavailable, the SAE/AESI must be reported to 
by telephone or fax
within 24 hours of becoming aware of the SAE and/or AESI as follows:
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SAE/AESI Hotline:
x
x
SAE/AESI Hotline Fax:
x
x
The investigator should not delay reporting because of missing information. Nonetheless, the 
report should be as complete as possible. This initial report should include, at a minimum, 
sufficient information to permit identification of the following:
x
The reporter (investigator’s name and contact information)
x
The subject
x
Involved trial medication
x
AE(s)
x
Seriousness criterion 
x
Date of onset
is responsible for expedited reporting to the involved regulatory authorities according to 
applicable laws and guidelines, and for safety report distribution to participating investigators,
IECs or IRBs and Human Research Protection Offices.
Regulatory authorities will be notified as soon as possible but no later than 7 days after date of 
first receipt of fatal or life-threatening SUSAR (Suspected Unexpected Serious Adverse 
Reaction) with an at least possible relationship to the IMP and no later than 15 days after 
knowledge of any non-fatal or non-life-threatening SUSAR.
11.14.2
Reporting of MAAEs
All MAAEs will be collected for the trial duration, including the follow-up period. MAAEs must 
be entered in the eCRF within 24 hours of awareness by the investigators. If an MAAE is 
considered serious or meets criteria for an AESI, reporting procedures in Section 11.14.1 are to 
be followed.
11.14.3 Reporting of Pregnancies
If a subject becomes pregnant during the active trial phase (up to and including 1 month 
[minimum 28 days] after receiving the trial vaccination), this must be reported to 
 within 
24 hours of the investigator becoming aware of the event (Section 11.13).
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A pregnancy will be followed to term, any premature terminations reported, and the health status 
of the mother and child including date of delivery and the child’s sex and weight will be reported 
by the investigator to
as soon as possible.
Any event during pregnancy fulfilling the criteria for an SAE or AESI will be reported to 
(see Section 11.14.1). However, hospitalization for delivery is a prospectively planned 
hospitalization and is not considered a SAE, per se.
12 Statistical Considerations
12.1 Randomization Procedure and Blinding Consideration, Part A Only
At Visit 1, subjects enrolled in Part A of the trial will be randomized in a 1:1 ratio to receive 
vaccination with a single 100 g dose of ABNCoV2 or a 30 g adult dose of Comirnaty,
stratified by age (<65 years versus 65 years) and prior vaccination regimens.
Randomization strata in Cohort 1 include the following prior vaccination regimens, completed at 
least 3 months prior to trial vaccination: 1) 2 doses of mRNA vaccine (Comirnaty or Spikevax),
2) 1 dose or 2 doses of adenovirus-based vaccine (Vaxzevria or Janssen COVID-19 Vaccine),
3) 1 dose of adenovirus-based vaccine followed within 3 months by 1 dose of mRNA vaccine,
and 4) other authorized primary vaccination regimen, if applicable.
Randomization strata in Cohort 2 include the following prior vaccination regimens, completed at 
least 3 months prior to trial vaccination: 1) 2 doses of mRNA primary vaccines plus 1 booster 
dose of mRNA vaccine (Comirnaty or Spikevax), 2) 1 dose or 2 doses of adenovirus-based 
primary vaccines (Vaxzevria or Janssen COVID-19 Vaccine) plus 1 booster dose of mRNA 
vaccine, and 3) other authorized primary vaccination and boost vaccination combinations.
Randomized assignments for subjects will be performed via an interactive voice or web response 
system (IVRS/IWRS) after confirmation of subject’s eligibility as specified in Section 1.3.
To minimize the potential for bias, site personnel and subjects are blinded to vaccination 
assignment. Additionally, the BN and CRO study teams and statistical programming team will 
not have unblinded data until database lock/freeze for the primary analyses.
12.2 Sample Size Calculation
12.2.1 Part A
The primary and key secondary analyses will be tested in the randomized, double-blind 
component of the trial (Part A) in both Cohort 1 and Cohort 2. Two non-inferiority tests will be 
performed. Therefore, the sample size calculation is based on a one-sided, 0.0125 type I error, Į,
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to control for both tests. This will maintain the trial-wide Į at 0.025 for the one-sided null 
inferiority hypotheses. 
Based on data from the ABNCoV2 phase 2 trial, we assume the common standard deviation to be 
0.52 for log10 transformed neutralizing antibody titers in both the ABNCoV2 and Comirnaty 
arms. The test of non-inferiority of ABNCoV2 compared with Comirnaty will be performed by 
comparing the lower end of the 97.5% CI with a non-inferiority margin of 0.67 in the ratio of 
neutralizing antibody GMTs between the two groups. We further assume a 10% non-evaluable 
rate due to dropouts or invalid samples. With an evaluable sample size of 450, a one-sided test 
with an Į of 0.0125 will have approximately 90% power to reject the null hypothesis that 
ABNCoV2 is inferior to Comirnaty.  
A minimum sample size of 400 evaluable subjects will be required for the non-inferiority 
hypothesis test to be performed for the primary endpoint within each cohort. In the event the 
evaluable sample size is as low as 400, the power to reject the null hypothesis that ABNCoV2 is 
inferior to Comirnaty is approximately 86%. In the event that the minimum sample size is not 
met in one of the cohorts regardless of recruitment effort, data from the cohort will be 
summarized descriptively and will be integrated in the combined-cohort analyses. 
For the key secondary analyses, the number of hypothesis tests to be performed will depend on 
the number of VOCs of interest circulating at the time of the trial. VOCs will only be formally 
tested sequentially in the separate Part A cohorts and in the 2 cohorts combined. Discussion of 
the gatekeeping procedures with regards to the multiple hypothesis tests for the key secondary 
endpoints is in Section 12.3. 
12.2.2 Part B 
The sample size for Part B is not based on formal statistical hypothesis testing, but rather on the 
number of subjects exposed to ABNCoV2 considered adequate for safety population analyses 
and may be adjusted depending on enrollment in Part A. A total of 3000 subjects (for example, 
2500 from Part B plus 500 from Part A who will receive ABNCoV2) would allow for 95% power 
to detect an AE with an incidence rate as low as 0.1%. 
The immunogenicity subset in Part B will consist of approximately 200 to 250 subjects in each 
cohort. This subset sample size is based on feasibility alone, i.e., the number of participating sites 
and consenting subjects. 
12.3 Multiplicity 
The hypothesis test of noninferiority of ABNCoV2 to Comirnaty in terms of neutralizing 
antibody titers for SARS-CoV-2 will be performed in Part A in up to 2 cohorts. A Bonferroni 
correction will be used to control the trial-wide type I error of Į = 0.025, one-sided. In the event a 
cohort does not meet the requirement of 400 evaluable subjects for the primary endpoint analysis, 
summaries for the under-enrolled cohort will be considered purely descriptive. 
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The key secondary endpoints, ratios of GMTs for the VOCs at 2 weeks after trial vaccination, 
will be formally tested in Part A for non-inferiority of ABNCoV2 to Comirnaty only in the 
cohort(s) in which the primary success criterion is met. If the primary success criterion is met in 
only one cohort, VOCs will be formally tested in that cohort only. A Bonferroni adjustment will 
be used such that each VOC non-inferiority hypothesis will be tested at the Į = 
଴.଴ଶହ
௡௨௠௕௘௥ ௢௙ ௏ை஼௦ ௧௘௦௧௘ௗ level. For example, if 3 VOCs are tested, each test will be performed at the Į 
= 0.0083 level such that success would require the lower confidence limit of a 98.3% CI to be at 
least 0.67. In the event that success criteria are met for both Cohort 1 and Cohort 2, the number of 
tests will multiply, and thus non-inferiority hypothesis will be tested at the Į = 
଴.଴ଵଶହ
௡௨௠௕௘௥ ௢௙ ௏ை஼௦ ௧௘௦௧௘ௗ level so that the overall type I error rate will be no more than 5%.  
12.4 Variables 
Endpoint variables are provided in Section 5. 
12.5 Analysis Populations 
The Safety Analysis Set for all safety endpoints and population-level summaries includes all 
subjects who received a trial vaccination with either ABNCoV2 or Comirnaty.  
The Immunogenicity Analysis Set for immunogenicity endpoints includes all subjects who are in 
the Safety Analysis Set, have at least a baseline and 1 post-vaccination neutralizing antibody titer 
result, have not tested positive for SARS-CoV-2 infection, and have not received a booster 
outside of the trial within 2 weeks of trial vaccination.  
12.6 Primary Analysis 
12.6.1 Primary Estimand 
The primary variable of interest is the subjects’ neutralizing antibody titers against the 
SARS-CoV-2 index virus measured at 2 weeks after trial vaccination in each Part A cohort, and 
the variable will be summarized as the ratio of GMTs for ABNCoV2 compared to Comirnaty in 
subjects meeting the immunogenicity analysis set definition. 
The planned primary analysis will be conducted in each of the Part A cohorts, and the null 
hypothesis of inferiority will be rejected if the ratio of GMTs is within the non-inferiority margin 
of 0.67, i.e., the lower limit of the 2-sided 97.5% CI of the GMT ratio is 0.67. 
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The following are considered intercurrent events: 
1) A positive test for SARS-CoV-2 infection prior to Visit 3 (12 to 16 days after 
vaccination), by PCR and 
2) Discontinuation from the trial due to AEs. 
For the primary estimand, the second intercurrent event is not considered as having an impact on 
the SARS-CoV-2 neutralizing antibody levels and therefore the “treatment policy” strategy will 
be used. Exposure to the virus can have significant effect on SARS-CoV-2 neutralizing antibody 
levels, and thus subjects who develop intercurrent infections will be excluded from the primary 
analysis. This is equivalent to the “while on treatment” strategy. Prior to database lock, a data 
review meeting will determine if any other intercurrent events (e.g., protocol violations) would 
affect the primary immunogenicity outcome and should result in exclusion of data points from 
the primary analysis. Strategies to handle these additional intercurrent events will be determined 
in a blinded fashion.  
12.6.2 Primary Analysis Methods 
The neutralizing antibody titers to the SARS-CoV-2 index virus will be collected and quantified 
as described in Section 10. As all subjects are previously vaccinated, it is not expected that a 
large number of titer values will be below the limits of quantitation or detection. In the case a titer 
result is below the limit of detection, a value of half the limit of detection will be used for 
analysis purposes. In the event a titer value is at least the limit of detection but below the limit of 
quantitation, a value of half the limit of quantitation will be used for analysis purposes. 
A generalized linear model will be used to compare the SARS-CoV-2 neutralizing antibody titers 
(on the log10 scale) at 2 weeks after trial vaccination between the vaccination groups with age and 
baseline titers included as covariates. The least squares means and the corresponding 97.5% CI 
from the model will be back transformed to their original scale via exponentiation for ease of 
interpretation. 
If the non-inferiority success criterion is met (lower bound of the 97.5% CI is 0.67), the p-value 
from the same model will be reported to assess superiority. 
12.6.3 Sensitivity and Supportive Analyses 
The primary analysis will be supported by descriptive summaries (GMT, their 95% CIs and the 
median) for each time point (pre- and post-vaccination). Besides summarizing data by cohort, 
summaries and the 95% CI will also be presented for combined Part A Cohorts 1 and 2. 
The proportion of subjects with 2-fold and 4-fold increase in neutralizing antibody titers to the 
SARS-CoV-2 index virus from baseline to 2 weeks after trial vaccination will be summarized 
using frequencies and percentages within cohort and arm. 
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Nucleocapsid protein test results will be used to perform additional sensitivity analyses of the 
primary endpoint. Test results that are indicative of SARS-CoV-2 infection will be used to 
exclude subjects from the analysis population as potential additional subjects experiencing the 
intercurrent event of COVID-19 infection prior to the 2 week timepoint. 
Since the window between vaccination and the primary endpoint measurement is short, the 
number of subjects with missing data is expected to be small. If there are any, missing data will 
be imputed using a multiple imputation method as a sensitivity analysis for subjects who meet the 
Safety Analysis Set definition. 
12.6.4 Subgroup Analyses 
The primary analysis will also be repeated for the following subgroups: prior vaccination regimen 
(per randomization strata in Section 12.1), age (<65 years and 65 years), baseline neutralizing 
titer to SARS-CoV-2 index virus (<Limit of Quantification, <median of all subjects in Part A, 
median of all subjects in Part A), time from previous vaccination, history of SARS-CoV-2 
infection and baseline comorbidity. If the number of subjects with known history of 
SARS-CoV-2 infection is small, the analysis for this subgroup will only be performed for 
subjects without known history of SARS-CoV-2 infection. 
12.7 Secondary Analyses 
12.7.1 Secondary Estimand 
The key secondary variables of interest are the subjects’ neutralizing antibody titers against 
circulating SARS-CoV-2 VOCs measured at 2 weeks after trial vaccination in Part A, and they 
will be summarized as the ratios of GMTs for ABNCoV2 compared to Comirnaty. 
The null hypothesis of inferiority will be rejected if the ratio of GMTs against the SARS-CoV-2 
VOCs, for ABNCoV2 vaccine compared to Comirnaty vaccine, is within the non-inferiority 
margin of 0.67. Only Part A cohort(s) that meet the primary success criterion will be formally 
tested sequentially for non-inferiority of ABNCoV2 to Comirnaty for each VOC, and a 
Bonferroni correction will be used to control the overall type I error rate for the trial. Details are 
provided in Section 12.3.  
The intercurrent events for the secondary analyses are the same as for the primary analysis and 
will be handled in a similar fashion (Section 12.6.1). 
Besides the key secondary variables of interest, other secondary variables include the subjects’ 
neutralizing antibody titers against the SARS-CoV-2 index virus measured at 2 weeks after 
ABNCoV2 vaccination in the immunogenicity subsets of Part B Cohort 1 and Cohort 2. These 
will be summarized descriptively using GMTs, 95% CIs, and medians. 
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12.7.2 Secondary Analysis Methods 
The VOCs for Part A will be analyzed using the same analysis methods as those for the primary 
estimand described in Section 12.6.2. The precision of the CIs will be adjusted based on the 
number VOCs included in the key secondary analyses. The decision regarding which VOCs to 
include will be finalized before sample analysis begins. The GMT ratios, adjusted CIs for the 
non-inferiority hypothesis testing, as well as 95% CIs will also be calculated as descriptive 
information. 
If the non-inferiority success criterion is met for a VOC (lower bound of the 97.5% CI is 0.67), 
the p-value from the same model will be reported to assess superiority. 
Analyses of other VOCs may also be performed similarly but not subjected to formal testing; 
such comparisons thus will not affect the trial-wide type I error. 
Analyses of Part B Cohort 1 and Cohort 2 will consist of descriptive summaries (GMTs, 95% 
CIs, and medians) for each time point (pre- and post-vaccination). 
12.7.3 Sensitivity and Supportive Analyses 
The same sensitivity and supportive analyses described for the primary estimand in 
Section 12.6.3 will also be repeated for each of the VOCs in Part A. Multiple imputation 
sensitivity analyses will only be performed for the Part A cohort formally tested for 
non-inferiority of ABNCoV2 to Comirnaty. 
12.7.4 Subgroup Analyses 
The same subgroup analyses described for the primary estimand in Section 12.6.4 will be 
performed for each of the VOCs in Part A. 
12.8 Exploratory Endpoints 
Geometric mean titers of neutralizing antibodies against the SARS-CoV-2 index virus and VOCs, 
along with their corresponding 95% CIs, will be summarized by time point and cohort for Part A 
to explore the kinetics of humoral responses over time. Like for the primary analysis, COVID-19 
infection is an intercurrent event for analyses of later time points due to its effect on humoral responses. 
Subjects with evidence of infection after the 2 week peak time point therefore will be removed from the 
Immunogenicity Analysis Set for these exploratory kinetic analyses. That is, not only will subjects with 
AEs of COVID-19 and positive PCR tests be removed, but additionally, due to the longer duration 
between follow-up visits and the possibility of asymptomatic COVID-19 infections, nucleocapsid protein 
testing will be used to remove subjects who have evidence of COVID-19 infection. Results will be 
presented in both tabular and graphical format. 
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Total antibody titers measured by ELISA in subsets of the Part A cohorts and cellular immune 
responses measured by ELISpot in the immunogenicity subsets of the Part B cohorts will also be 
summarized using geometric means and their 95% CIs. The difference between the ABNCoV2 
and Comirnaty vaccination groups in the Part A cohorts with respect to total antibody titers will 
also be described by the ratio of their GMTs (ABNCoV2 vs. Comirnaty) and corresponding 95% 
CIs within each cohort. All analyses will be considered descriptive. The GMTs and 95% CIs will 
also be plotted as a function of time for each assay and vaccination group for the applicable parts 
and cohorts on the log10 scale. 
Fold increases, defined as post-baseline titers divided by the baseline titers, will be summarized 
by assay, vaccination group (if applicable), and timepoint within each part and cohort. They will 
further be summarized by subgroups (age, baseline titer category, baseline comorbidity, previous 
vaccination regimen, history of known SARS-CoV-2 infection, and time from previous 
vaccination). Similar to the titers, fold increases will also be summarized by geometric means and 
corresponding 95% CIs. 
The combined cohort analyses for Part A will be similar to the analyses performed for each 
cohort. 
12.9 Analyses of Safety 
Safety data will be summarized descriptively. Adverse event data will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Solicited and unsolicited AEs will be 
summarized by system organ class, preferred term, and cohort. Solicited and unsolicited AEs that 
meet certain criteria, e.g., Grade 3, serious, related to vaccination, within 8 days after trial 
vaccination, or during the active trial phase, will be summarized similarly. 
Based on AE and SARS-CoV-2 PCR testing results in Part A, the proportion of subjects testing 
positive for COVID-19 infection by timepoint, and at any time after trial vaccination, will be 
summarized by vaccination group for each of the cohorts. For Part B, proportions will be 
summarized for each cohort by timepoint and overall. 
Vital signs and laboratory data will be graded according to the scales in “Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
(FDA, 2007) and reported by toxicity type and grade. Summaries will focus on subject level 
changes, thus shifts from baseline in toxicity grade or normal range indicator will be summarized 
by vaccination group and cohort.  
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12.10 Timing of Analyses 
12.10.1 Primary Analysis 
The primary analysis for the trial will occur after all subjects have completed the 2 months of 
follow up. All planned immunogenicity and safety analyses will be performed. A data review 
meeting will take place once all data are entered into the database prior to database lock. Once 
the trial data are clean and any queries resulting from the data review meeting are resolved, the 
database will be locked and unblinded for the analysis. A full CSR will be written for this 
analysis. 
12.10.2 Final Analysis 
The data collected at the 3 month and 6 month follow up visits will be analyzed at the end of the 
trial after the database lock. As limited immunogenicity and safety data are collected at these 
time points, a CSR addendum may be written in place of a full CSR.  
13 Ethical Aspects 
13.1 Ethical and Legal Regulations 
The PI is to ensure that this clinical trial is conducted in complete accordance with the provisions 
of the 2013 version of the Declaration of Helsinki, national laws, and other guidelines for the 
conduct of clinical trials, such as the ICH Good Clinical Practice (GCP), to guarantee the greatest 
possible subject protection. 
13.2 Approval by IEC/IRB 
The clinical trial protocol must be reviewed by the competent IEC/IRB according to the national 
laws of the respective CTS before the CTS enrolls its first subject in the trial. 
If one of the investigators is a member of one of these committees, he/she may not vote on any 
aspect of the review of this protocol. 
The Sponsor will assure that the IEC/IRB is informed of any amendment to the protocol and any 
unanticipated problems involving risks to human subjects included in the trial. Such information 
will be provided to the IEC/IRB at intervals appropriate to the degree of subject risk involved, but 
not less than once a year. Copies of all correspondence between the investigator and the IEC/IRB 
must be forwarded immediately to the Sponsor. If IEC/IRB approval of the trial is withdrawn, the 
Sponsor must be contacted immediately by facsimile, e-mail or telephone. 
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13.3 Data and Safety Monitoring
13.3.1 Data Monitoring Committee
The DMC is an independent board that oversees the safety of subjects participating in the trial. 
The members of the DMC are independent experts with experience in infectious diseases. The 
primary responsibility of the DMC is to review and evaluate the accumulated trial safety data and 
make recommendations whether to continue the trial to its planned conclusion.
If an event occurs which fulfills the trial halting rules (see Section 13.3.2 for further details), the
DMC will review the event in a timely manner and agree whether to recommend halting or
terminating the trial participation of the affected subject(s) and/or the trial as a whole. If the trial 
as a whole or participation of specific subjects is halted, the DMC also will decide if and when to 
recommend resuming the trial or subject participation in it.
A separate charter will describe in detail the relevant operational procedures, communication 
pathways, roles and responsibilities of the DMC.
13.3.2 Stopping Rules
The events or criteria listed below would trigger a DMC review to determine whether a
temporary halting or termination for the trial as a whole is warranted:
x
A serious AESI or other SAE with an at least reasonable possibility of a causal relationship 
to the administration of trial vaccine
x
An unexpected Grade 3 or higher adverse event (e.g., a systemic reaction or lab toxicity)
with at least a reasonable possibility of a causal relationship to the administration of trial 
vaccine
x
Any case of myocarditis or pericarditis in temporal association to the administration of trial
vaccine
The Medical Monitor or safety physician will review cases of Grade 3 or higher adverse events at 
least weekly. Any issues identified during this review can be brought to the DMC for review. 
In general, any member of the DMC, the PI, and/or the BN Medical Monitor or safety physician 
may request a DMC review based on any observation. The DMC Chair may convene an ad-hoc 
meeting to review events and make recommendations with respect to the study whether or not the
study stopping rules are met.
If an event fulfilling the DMC review criteria reaches the investigator’s attention, the investigator 
has the responsibility to alert the Clinical Safety and Pharmacovigilance (CSPV) Department at 
email 
within 24 hours and provide comprehensive 
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documentation of the event. A DMC meeting should be convened within 48 hours after the 
sponsor receives the relevant safety information. 
13.4 Confidentiality and Data Protection 
The PI of the respective CTS is obliged to make sure that all documents provided to third parties 
(e.g., in the course of a marketing authorization procedure) contain no personally identifying 
information. 
Only a subject and site number may identify subjects. Their name or clinic and subject’s medical 
record number may not be used. The PI keeps a separate confidential subject log for trial 
recruitment that allows subject numbers to be matched with names and addresses of subjects at 
any time. Documents not meant to be passed on to third parties must be stored securely by the PI. 
Information collected during the trial may be made available to persons directly involved in this 
trial (PI and his staff members, monitors, statisticians), to persons authorized by the Sponsor, or 
to authorities. The Sponsor of the trial will only receive pseudonymized data for analysis. 
14 Informed Consent 
The ICF and process must comply with ICH GCP guidelines, as well as specific national 
regulations and/or local laws in the countries where the trial is conducted and must be approved 
by the appropriate IEC/IRB. 
The ICF will document the trial-specific information that the investigator or his/her designee 
(designee must be listed on the Delegation of Authority log) provides to the subject and the 
subject’s agreement to participate. The investigator, or designee, must explain in terms 
understandable to the subject the purpose and nature of the trial, trial procedures, anticipated 
benefits, potential risks, possible adverse effects, and any discomfort that participation in the trial 
may entail.  
Subjects must be informed unequivocally that they may refuse participation in the trial, that they 
may withdraw from the trial at any time and for whatever reason, and that withdrawal of consent 
will not affect their subsequent medical treatment or relationship with the treating physician. 
Subjects also consent to authorize the monitor, quality assurance personnel, and regulatory 
authorities to inspect source documents for data verification and quality assurance purposes. Such 
verifications will always be conducted in compliance with regulations and the terms of the 
informed consent and under the ethical supervision of the investigator. All aspects of the 
confidentiality of the subject’s data will be guaranteed. 
This ICF process must be documented in the subject’s source record. Each subject must provide a 
signed and dated informed consent before any trial-related (nonstandard of care) activities are 
performed (such as baseline testing and data collection). The initial and any amended signed and 
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dated consent forms must remain in each subject’s trial file at the CTS and be available for 
verification by trial monitor, Sponsor/CRO auditor or competent regulatory authorities at any 
time. A copy of each signed consent form must be given to the subject at the time that it is signed 
by the subject. 
15 Electronic Case Report Forms and Retention of Records 
15.1 Electronic Case Report Forms 
Electronic case report forms will be used to collect the clinical trial data. 
All eCRFs are to be filled out completely by authorized CTS personnel. It is the investigator’s 
responsibility to ensure that all subject data entered in the eCRF (including discontinuations or 
changes in trial vaccine or other medications) are accurate, complete and supported by the 
subject’s medical records. The investigator attests to this by providing electronic signature within 
the electronic data capture (EDC) system. 
All effort will be made by trial personnel and the PI to enter the eCRFs within the contractually 
agreed-upon time frame for subject visits/contacts. For any subject leaving the trial, any 
remaining eCRF and open queries should be completed at the time of the final visit or shortly 
thereafter. For subjects not fulfilling the eligibility criteria, the minimum information documented 
in the eCRF is the ICF information, demographics, and reason for screen failure. 
The eCRFs exist within an EDC system with controlled access managed by BN or its authorized 
representative for this trial. Trial staff will be appropriately trained in the use of eCRFs and 
application of electronic signatures before the start of the trial and before being given access to 
the EDC system. Original data and any changes of data will be recorded using the EDC system, 
with all changes tracked by the system and recorded in an electronic audit trail. After database 
lock, the investigator will receive a copy of the subject data (e.g., paper, CD-ROM or other 
appropriate media) for archiving at the CTS. 
15.2 Retention of Records 
The investigator/trial staff must maintain adequate and accurate records to enable the conduct of 
the trial to be fully documented and the trial data to be subsequently verified. All essential 
documents, as listed in ICH GCP guidelines, will be retained by the investigator for at least 
2 years after the date the last marketing application is approved for the drug in the indication 
being investigated and until there are no pending or contemplated marketing applications; or, if 
no application is to be filed or if the application is not approved for such indication, until 2 years 
after formal discontinuation of clinical development of the drug.  
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The investigator must notify and obtain written approval from BN before destroying any clinical 
trial documents or images (e.g., scan, radiograph, ECG tracing). The Sponsor will inform the 
investigator of the date that the trial records may be destroyed or returned to BN.  
Should an investigator wish to assign trial records to another party, advance written notice must 
be given to the Sponsor. Bavarian Nordic must also be notified in advance and provide express 
written approval of any change in the maintenance of clinical trial documents, should the 
investigator choose to move trial records to another location.  
If the investigator cannot guarantee the aforementioned archiving requirements at the CTS for all 
such documents, special arrangements must be made between the investigator and BN to store 
these documents in secure sealed containers away from the CTS. These documents must be able 
to be returned in their secure sealed containers to the CTS for auditing purposes. 
16 Monitoring of the Trial 
16.1 Monitoring Plan 
A CRO (contact information to be found in the “Responsibilities” section in the beginning of this 
protocol) will be contracted to perform monitoring services according to ICH GCP. Monitoring 
will be conducted according to the monitoring plan, which must be approved by BN. The 
monitoring plan will outline the monitoring strategy (including rationale) and will specify in 
detail the items for source data verification and other tasks, to be performed by the CRA. 
Monitoring will be conducted through onsite visits with the investigator and site staff, remote 
monitoring, as well as any appropriate communications by mail, fax, email, or telephone. The 
purpose of monitoring is to ensure that the trial is conducted in compliance with the protocol, 
SOPs, and other written instructions and regulatory guidelines, and to ensure the quality and 
integrity of the data.  
To assure the accuracy of data collected in the eCRFs, it is mandatory that the monitor have 
direct access to all original source documents, including all electronic medical records at 
reasonable times and upon reasonable notice. During the review of source documents, every 
effort will be made to maintain the privacy and confidentiality of all subjects during this clinical 
trial.  
The site needs to maintain records to identify the nature and location of all source documents as 
well as essential documents.  
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16.2 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol. The noncompliance 
may be either on the part of the participant, the investigator, or the trial site staff. As a result of 
deviations, corrective actions are to be developed by the site and implemented promptly.  
The PI or designee will be responsible for identifying and recording all deviations that are 
defined as isolated occurrences involving a procedure that did not follow the protocol or a 
protocol-specific procedure. All deviations from the protocol and actions taken will be recorded 
in the source data and placed in the trial-specific regulatory file. Protocol deviations must be sent 
to the local IEC/IRB per their guidelines. The site PI/trial staff is responsible for knowing and 
adhering to their IEC/IRB requirements. Further details about the handling of protocol deviations 
will be included in a trial-specific procedure. 
17 Audits and Inspections 
Site audits may be carried out by the BN quality assurance department or designee at any time 
during or after completion of this trial. All documents pertinent to the trial must be made 
available to the designated auditor. Subject privacy must, however, be respected. The investigator 
and clinical staff are to be present and available for consultation during routinely scheduled site 
audit visits conducted by the Sponsor or designee. 
In addition, representatives from local, state, or federal regulatory authorities may choose to 
inspect a trial site at any time before, during, or after completion of the clinical trial. The 
investigator should immediately notify the Sponsor if they have been contacted by a regulatory 
agency concerning an upcoming inspection. In the event of such an inspection, BN will be 
available to assist in the preparation. All pertinent trial data should be made available as 
requested by the Regulatory Authority for verification, audit, or inspection purposes. 
18 Responsibility of the Investigator 
The investigator should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the trial, should meet all the qualifications specified by 
the applicable regulatory requirement(s), and should provide evidence of such qualifications 
through up-to-date curriculum vitae or other relevant documentation requested by the Sponsor, 
the IRB/IEC, or the regulatory authority(ies). 
The PI agrees to carry out the trial in accordance with the guidelines and procedures outlined in 
this clinical trial protocol. The PI especially consents to strictly adhere to the ethical aspects of 
this protocol (see Section 13). 
Changes to the protocol require written “Amendments to the protocol” issued by the Sponsor and 
written approval by the IEC/IRB and the PI. Changes are allowed only if the trial value is not 
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reduced and if they are ethically justifiable. If required by the IEC/IRB, subjects will be informed 
of protocol changes and reconsented regarding changes that could affect subjects’ willingness to 
continue participation in the trial. 
It is within the responsibility of the investigator to ensure that the eCRF is completed in a timely 
manner after each subject visit and that all subject data entered in the eCRF are accurate, 
complete, and supported by the subject’s medical records. The investigator attests to this by 
providing electronic signature within the electronic data capture (EDC) system. 
At the conclusion of the trial, the investigator will return all partially used, unused and empty 
drug containers as directed by BN, or the drug containers will be destroyed at the CTS according 
to local legal requirements.  
The investigator may ask to terminate participation in the trial due to administrative or other 
reasons. If this should be the case, appropriate measures that safeguard the interests of the 
participating subjects must be taken after verification and consultation with the PI. 
The investigator will maintain appropriate medical and research records for this trial, in 
compliance with the ICH E6 Guideline for GCP and regulatory and institutional requirements for 
the protection of confidentiality of subjects. He/she will permit authorized representatives of the 
Sponsor and regulatory authorities to review (and, when required by applicable law, to copy) 
clinical records for the purposes of quality reviews, audits/inspections, and evaluation of the trial 
safety and progress. 
The PI agrees to follow the detailed publication policy included in the clinical trial agreement. 
By signing this protocol, the PI confirms that he/she has read the entire clinical trial protocol, 
agrees to its procedures, and will comply strictly with the formulated guidelines. 
 
 
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19 References 
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JANITZEK, C. M., SOGAARD, M., AVES, K. L., HORSTED, E. W., ERDOGAN, S. 
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GILBERT, P. B., MONTEFIORI, D. C., MCDERMOTT, A., FONG, Y., BENKESER, D., 
DENG, W., ZHOU, H., HOUCHENS, C. R., MARTINS, K., JAYASHANKAR, L., 
CASTELLINO, F., FLACH, B., LIN, B. C., O'CONNELL, S., MCDANAL, C., EATON, 
A., SARZOTTI-KELSOE, M., LU, Y., YU, C., BORATE, B., VAN DER LAAN, L. W. 
P., HEJAZI, N., HUYNH, C., MILLER, J., EL SAHLY, H. M., BADEN, L. R., BARON, 
M., DE LA CRUZ, L., GAY, C., KALAMS, S., KELLEY, C. F., KUTNER, M., 
ANDRASIK, M. P., KUBLIN, J. G., COREY, L., NEUZIL, K. M., CARPP, L. N., 
PAJON, R., FOLLMANN, D., DONIS, R. O. & KOUP, R. A. 2021. Immune Correlates 
Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Trial. medRxiv. 
JANITZEK, C. M., MATONDO, S., THRANE, S., NIELSEN, M. A., KAVISHE, R., 
MWAKALINGA, S. B., THEANDER, T. G., SALANTI, A. & SANDER, A. F. 2016. 
Bacterial superglue generates a full-length circumsporozoite protein virus-like particle 
vaccine capable of inducing high and durable antibody responses. Malar J, 15, 545. 
MUNRO, A. P. S., JANANI, L., CORNELIUS, V., ALEY, P. K., BABBAGE, G., BAXTER, D., 
BULA, M., CATHIE, K., CHATTERJEE, K., DODD, K., ENEVER, Y., GOKANI, K., 
GOODMAN, A. L., GREEN, C. A., HARNDAHL, L., HAUGHNEY, J., HICKS, A., 
VAN DER KLAAUW, A. A., KWOK, J., LAMBE, T., LIBRI, V., LLEWELYN, M. J., 
MCGREGOR, A. C., MINASSIAN, A. M., MOORE, P., MUGHAL, M., MUJADIDI, Y. 
F., MURIRA, J., OSANLOU, O., OSANLOU, R., OWENS, D. R., PACURAR, M., 
PALFREEMAN, A., PAN, D., RAMPLING, T., REGAN, K., SAICH, S., SALKELD, J., 
SARALAYA, D., SHARMA, S., SHERIDAN, R., STURDY, A., THOMSON, E. C., 
TODD, S., TWELVES, C., READ, R. C., CHARLTON, S., HALLIS, B., RAMSAY, M., 
ANDREWS, N., NGUYEN-VAN-TAM, J. S., SNAPE, M. D., LIU, X., FAUST, S. N. & 
GROUP, C.-B. S. 2021. Safety and immunogenicity of seven COVID-19 vaccines as a 
third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK 
(COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial. Lancet, 
398, 2258-2276. 
NIH. 2021. Clinical spectrum of SARS-CoV-2 infection [Online].  
PASTORI, C., TUDOR, D., DIOMEDE, L., DRILLET, A. S., JEGERLEHNER, A., ROHN, T. 
A., BOMSEL, M. & LOPALCO, L. 2012. Virus like particle based strategy to elicit HIV-
protective antibodies to the alpha-helic regions of gp41. Virology, 431, 1-11. 
ROBBIANI, D. F., GAEBLER, C., MUECKSCH, F., LORENZI, J. C. C., WANG, Z., CHO, A., 
AGUDELO, M., BARNES, C. O., GAZUMYAN, A., FINKIN, S., HAGGLOF, T., 
OLIVEIRA, T. Y., VIANT, C., HURLEY, A., HOFFMANN, H. H., MILLARD, K. G., 
KOST, R. G., CIPOLLA, M., GORDON, K., BIANCHINI, F., CHEN, S. T., RAMOS, 
V., PATEL, R., DIZON, J., SHIMELIOVICH, I., MENDOZA, P., HARTWEGER, H., 
NOGUEIRA, L., PACK, M., HOROWITZ, J., SCHMIDT, F., WEISBLUM, Y., 
MICHAILIDIS, E., ASHBROOK, A. W., WALTARI, E., PAK, J. E., HUEY-TUBMAN, 
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K. E., KORANDA, N., HOFFMAN, P. R., WEST, A. P., JR., RICE, C. M., 
HATZIIOANNOU, T., BJORKMAN, P. J., BIENIASZ, P. D., CASKEY, M. & 
NUSSENZWEIG, M. C. 2020. Convergent antibody responses to SARS-CoV-2 in 
convalescent individuals. Nature, 584, 437-442. 
SEXSON TEJTEL, S. K., MUNOZ, F. M., AL-AMMOURI, I., SAVORGNAN, F., GUGGILLA, 
R. K., KHURI-BULOS, N., PHILLIPS, L. & ENGLER, R. J. M. 2022. Myocarditis and 
pericarditis: Case definition and guidelines for data collection, analysis, and presentation 
of immunization safety data. Vaccine, 40, 1499-1511. 
SHANG, J., WAN, Y., LUO, C., YE, G., GENG, Q., AUERBACH, A. & LI, F. 2020a. Cell entry 
mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A, 117, 11727-11734. 
SHANG, J., YE, G., SHI, K., WAN, Y., LUO, C., AIHARA, H., GENG, Q., AUERBACH, A. & 
LI, F. 2020b. Structural basis of receptor recognition by SARS-CoV-2. Nature, 581, 221-
224. 
THRANE, S., JANITZEK, C. M., MATONDO, S., RESENDE, M., GUSTAVSSON, T., DE 
JONGH, W. A., CLEMMENSEN, S., ROEFFEN, W., VAN DE VEGTE-BOLMER, M., 
VAN GEMERT, G. J., SAUERWEIN, R., SCHILLER, J. T., NIELSEN, M. A., 
THEANDER, T. G., SALANTI, A. & SANDER, A. F. 2016. Bacterial superglue enables 
easy development of efficient virus-like particle based vaccines. J Nanobiotechnology, 14, 
30. 
TISSOT, A. C., RENHOFA, R., SCHMITZ, N., CIELENS, I., MEIJERINK, E., OSE, V., 
JENNINGS, G. T., SAUDAN, P., PUMPENS, P. & BACHMANN, M. F. 2010. Versatile 
virus-like particle carrier for epitope based vaccines. PLoS One, 5, e9809. 
VOJDANI, A. & KHARRAZIAN, D. 2020. Potential antigenic cross-reactivity between SARS-
CoV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clin 
Immunol, 217, 108480. 
WALLS, A. C., PARK, Y. J., TORTORICI, M. A., WALL, A., MCGUIRE, A. T. & VEESLER, 
D. 2020. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. 
Cell, 181, 281-292.e6. 
WRAPP, D., WANG, N., CORBETT, K. S., GOLDSMITH, J. A., HSIEH, C. L., ABIONA, O., 
GRAHAM, B. S. & MCLELLAN, J. S. 2020. Cryo-EM structure of the 2019-nCoV spike 
in the prefusion conformation. Science, 367, 1260-1263. 
WU, F., WANG, A., LIU, M., WANG, Q., CHEN, J., XIA, S., LING, Y., ZHANG, Y., XUN, J., 
LU, L., JIANG, S., LU, H., WEN, Y. & HUANG, J. 2020. Neutralizing antibody 
responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their 
implications. medRxiv, 2020.03.30.20047365. 
 
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20 Appendices 
Appendix 1: Toxicity Scale for Laboratory Values 
Grade 1 or Grade 2 toxicity is only graded according to “Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials”  if the value is 
outside of the institutional normal range applicable for this trial. 
Estimating severity grade 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
Grade 1 
An AE which is easily tolerated by the subject, causing minimal discomfort and 
not interfering with daily activities. 
 
Grade 2 
An AE which is sufficiently discomforting to interfere with daily activities, but 
does not require medical intervention (non-narcotic pain reliever or other 
nonprescription medication are not considered “medical intervention” for this 
purpose). 
 
Grade 3 
An AE which prevents daily activities, and which requires medical intervention 
(non-narcotic pain reliever or other nonprescription medication are not considered 
“medical intervention” for this purpose). 
 
Grade 4 
Life-threatening or disabling 
 
Serious or life-threatening AEs 
ANY clinical event deemed by the clinician to be serious or life-threatening should be considered 
a Grade 4 event. Clinical events considered to be serious or life-threatening include, but are not 
limited to: Seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, severe depression. 
 
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Appendix 2: Grading Scale for Lymphadenopathy 
A grading scale for lymphadenopathy would apply as follows: 
Grade 0 (normal finding): 
No palpable lymph nodes or lymph nodes up to a diameter of 
1 cm, soft, non-tender  
Grade 1 (mild): 
 
Slightly palpable lymph nodes or lymph nodes up to a diameter 
of 1 cm, bilaterally enlarged lymph nodes, signs of tenderness 
Grade 2 (moderate): 
 
Markedly palpable lymph nodes or lymph node diameter 
exceeds 1 cm, bilaterally enlarged lymph nodes, pain, skin 
redness, warmth, limiting instrumental daily life activities 
Grade 3 (severe): 
Markedly palpable lymph nodes or lymph node diameter 
exceeds 2 cm, generalized enlargement of lymph nodes, severe 
pain, general symptoms like fever and sweating limiting self-
care daily activities 
 
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Appendix 3: Myocarditis and Pericarditis Scale, Case Definitions for COVID-19 Adverse Events of Special 
Interest, Brighton Collaboration 
Brighton Collaboration publications are provided at the link below: 
Brighton Collaboration Publications - Google Sheets 
As of the date of this protocol edition, case definitions have been published for the below AESIs at the links provided in Table 4, 
which were excerpted from the above website. 
Table 4 
Brighton Collaboration Publications of COVID-19 AESI Case Definitions 
Publication Organization 
Information on Publication 
Case Definition 
Companion Guidea 
Category 
Sub-category 
Title 
Year 
PMID 
DOI 
Link 
Cardiac 
Myocarditis 
Pericarditis  
Myocarditis and pericarditis: Case 
definition and guidelines for data 
collection, analysis, and presentation of 
immunization safety data 
2022 
35105494 
10.1016/j.vaccine.2021.11.074 
Myocarditis and 
Pericarditis Case 
Definition 
Companion Guide 
Hematologic 
Thrombocytopenia 
Thrombocytopenia: case definition and 
guidelines for collection, analysis, and 
presentation of immunization safety data. 
2007 
17493712 
10.1016/j.vaccine.2007.02.067 
Thrombocytopenia 
Case Definition 
Companion Guide 
Neurologic 
Aseptic meningitis 
Aseptic meningitis: case definition and 
guidelines for collection, analysis and 
presentation of immunization safety data. 
2007 
17574313 
10.1016/j.vaccine.2007.04.058 
Aseptic Meningitis 
Case Definition 
Companion Guide 
Neurologic 
Encephalitis / 
myelitis / ADEM 
Encephalitis, myelitis, and acute 
disseminated encephalomyelitis (ADEM): 
case definitions and guidelines for 
collection, analysis, and presentation of 
immunization safety data. 
2007 
17570566 
10.1016/j.vaccine.2007.04.060 
Myelitis Case 
Definition 
Companion Guide 
ADEM Case 
Definition 
Companion Guide 
Acute Encephalitis 
Case Definition 
Companion Guide 
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Publication Organization 
Information on Publication 
Case Definition 
Companion Guidea 
Category 
Sub-category 
Title 
Year 
PMID 
DOI 
Link 
Neurologic 
Facial nerve palsy 
Facial nerve palsy including Bell's palsy: 
Case definitions and guidelines for 
collection, analysis, and presentation of 
immunisation safety data 
2017 
27235092 
10.1016/j.vaccine.2016.05.023 
Facial Nerve Palsy 
Case Definition 
Companion Guide 
Neurologic 
Guillain Barre 
Syndrome (GBS) 
Guillain-Barre syndrome and Fisher 
syndrome: case definitions and guidelines 
for collection, analysis, and presentation of 
immunization safety data 
2011 
20600491 
10.1016/j.vaccine.2010.06.003 
GBS and Miller 
Fisher Syndrome 
Case Definition 
Companion Guide 
Neurologic 
Seizure 
Generalized convulsive seizure as an 
adverse event following immunization: 
case definition and guidelines for data 
collection, analysis, and presentation 
2004 
14741144 
10.1016/j.vaccine.2003.09.008 
Generalized 
Convulsion Case 
Definition 
Companion Guide 
Neurologic 
Sensorineural 
hearing loss 
(SNHL) 
Sensorineural hearing loss (SNHL) as an 
adverse event following immunization 
(AEFI): Case definition & guidelines for 
data collection, analysis, and presentation 
of immunization safety data 
2020 
32418788 
10.1016/j.vaccine.2020.05.019 
 
Respiratory 
ARDS 
Acute respiratory distress syndrome 
(ARDS) as an adverse event following 
immunization: Case definition & 
guidelines for data collection, analysis, 
and presentation of immunization 
safety data 
2021 
33583673 
10.1016/j.vaccine.2021.01.053 
 
Systemic 
VAED 
Vaccine-associated enhanced disease: Case 
definition and guidelines for data 
collection, analysis, and presentation of 
immunization safety data 
2021 
33637387 
10.1016/j.vaccine.2021.01.055 
 
Systemic 
reactions 
Anaphylaxis 
Anaphylaxis: case definition and 
guidelines for data collection, analysis, and 
presentation of immunization safety data 
2007 
17448577 
10.1016/j.vaccine.2007.02.064 
Anaphylaxis Case 
Definition 
Companion Guide 
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Publication Organization 
Information on Publication 
Case Definition 
Companion Guidea 
Category 
Sub-category 
Title 
Year 
PMID 
DOI 
Link 
Vasculitis 
Single organ 
cutaneous 
vasculitis 
Single organ cutaneous vasculitis: Case 
definition & guidelines for data collection, 
analysis, and presentation of immunization 
safety data 
2016 
28029543 
10.1016/j.vaccine.2016.09.032 
 
a Where case definitions are provided in supplemental materials, links to the case definition companion guides are provided. 
 
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Appendix 4: Adverse Event Follow-up Questionnaire — Inflammatory 
Cardiac Disorders 
Please enter all dates in the following format: DD/MMM/YYYY (e.g., 01/MAR/2019) 
Patient 
Initials/Subject ID         
Sex  
  M     
  
F 
DOB        
Study ID (if applicable)        
Suspect Product Administration 
ABNCoV2  
Date of dose        
Batch no.        
 Comirnaty 
Date of dose        
Batch no.        
 
 
 
 
 
 
 
 
 
Other (specify):       
Therapy dates 
       
Dose/frequency: 
      
Indication        
Other (specify):       
Therapy dates 
       
Dose/frequency: 
      
Indication        
Cardiovascular Adverse Event(s) – enter a diagnosis or signs/symptoms if a diagnosis is not available 
Cardiovascular Adverse Events(s) 
New 
onset 
(Y/N) 
Start Date 
Stop 
Date 
CTCAE 
Gradea 
Serious 
Criteriab 
 
Outcomec  
      
 
      
      
      
      
      
      
 
      
      
      
      
      
      
 
      
      
      
      
      
Key symptoms (mark N/A if not 
present) 
 
Start Date 
Stop 
Date 
CTCAE 
Gradea 
Serious 
Criteriab 
Outcomec  
Cough 
 
      
      
      
      
      
Dizziness/Fainting 
 
      
      
      
      
      
Dyspnea 
 
      
      
      
      
      
Palpitations 
 
      
      
      
      
      
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Chest pain, pressure or discomfort  
 
      
      
      
 
      
Typical chest pain made worse when 
lying down and relieved by sitting up 
 
      
      
      
      
Any other symptoms, please specify 
 
Key: 
CTCAE Gradea 
1 = Grade 1 (mild) 
2 = Grade 2 
(moderate) 
3 = Grade 3 (severe) 
4 = Grade 4 (life-
threatening) 
5 = Fatal 
Serious Criteriab 
D = Death 
L = Life-threatening 
H = Hospitalization/prolonged 
hospitalization 
S = Significant disability 
M = Medically significant 
N/A = Not applicable (non-serious) 
Outcomec 
1 = Recovered/resolved 
2 = Recovering/resolving 
3 = Not recovered/not resolved 
4 = Recovered/resolved with sequelae 
5 = Fatal 
6 = Unknown 
If one of the events resulted in death  
Date of death:       
Cause:       
Was an autopsy performed?  
 
 No  
 Yes (if available please attach report) 
Hospitalization  
 
 
Admission date:        
 
Discharge Date:       
Cardiac Diagnostic Results – enter N/A if not performed 
Test Method 
Test 
Date 
Test Results 
(please include reference range for lab values) 
Chest X-ray 
      
      
Auscultation 
      
      
ECG 
      
      
Echocardiography 
      
      
Troponin I or T 
      
      
Cardiac MRI 
      
      
Cardiac CT scan 
      
      
Pericardial Endomyocardial 
biopsy 
      
      
Other diagnostic tests (please specify, e.g., Angiography, Ergometry, etc.) 
      
      
      
      
      
      
      
      
      
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Was any pericardial 
effusion identified?  
 Yes 
 No 
If yes, please provide details (date, how diagnosed, estimated volume etc.):       
Was an endomyocardial 
biopsy performed?  
 Yes 
 No 
If yes, please provide details (date, histology results etc.): 
      
Minimum left ventricular 
ejection fraction (LV-EF) 
       
% 
Date and method of measurement:       
Were vasopressors or positive inotropic agents administered?  
 Yes  
 No 
Name of treatment 
Route 
Dose 
Therapy Dates 
Response 
      
      
      
      
      
      
      
      
      
      
Were any other agents to treat heart failure administered?  
 Yes  
 No 
(e.g., diuretics, vasodilators, ACE inhibitors, ß-blocking agents, etc.) 
Name of treatment 
Route 
Dose 
Therapy Dates 
Response 
      
      
      
      
      
      
      
      
      
      
Were any other treatments administered?   
 Yes  
 No 
Name of treatment 
Route 
Dose 
Therapy Dates 
Response 
      
      
      
      
      
      
      
      
      
      
Were any non-drug treatments applied?  
 Yes  
 No 
Description of treatment 
Therapy Dates 
Response 
      
      
      
      
      
      
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Risk factors (list below) or  
  No risk factors 
Recent episodes of viral 
(e.g., adeno, coxsackie), 
bacterial or fungal 
infections 
 Yes 
 No 
If yes, please provide details       
Chronic infections (e.g. HIV, 
tuberculosis, Hepatitis B/C) 
 Yes 
 No 
If yes, please provide details       
Previous hypersensitivities 
(incl. but not limited to 
sulfonamides, NSAIDs 
etc.)? 
 Yes 
 No 
If yes, please provide details       
Previous autoimmune 
disorders (e.g. celiac 
disease, rheumatoid 
diseases, etc.) 
 Yes 
 No 
If yes, please provide details       
History of malignancies 
(e.g. incl. anthracyclin 
treatment) 
 Yes 
 No 
If yes, please provide details       
Known ischemic disorders, 
incl. cardiac/coronary 
 Yes 
 No 
If yes, please provide details       
Chronic alcohol or tobacco 
use 
 Yes 
 No 
If yes, please provide details       
Recent pregnancy (female 
patients) 
 Yes 
 No 
If yes, please provide details       
Family history of 
inflammatory cardiac 
disorders? 
 Yes 
 No 
If yes, please provide details       
Other risk factors (specify): 
      
 Yes 
 No 
If yes, please provide details       
Medical History potentially relevant for assessment of cardiac conditions, in addition to the risk factors specifically listed 
above: 
Condition 
Start date, intensity, treatments, further relevant details 
      
      
      
      
      
      
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Relevant current condition: Please indicate below whether the patient currently has, or has 
had in the past, any of the following cardiovascular conditions. If any apply, please provide 
the additional details requested 
Condition 
Yes/No/Unk Start 
date 
Stop 
date 
Ongoing 
(Yes/No) 
Details, including treatments received 
Myocarditis 
 
 
 
 
 
Pericarditis 
 
 
 
 
 
Hypertension 
 
 
 
 
 
Thrombosis 
 
 
 
 
 
Cardiac arrhythmia 
 
 
 
 
 
Myocardial infacrtion 
 
 
 
 
 
Coronary artery 
disease 
 
 
 
 
 
Other heart/vascular 
condition (specify) 
 
 
 
 
 
Bacterial Infections in 
the last 6 months (e.g., 
Streptococcal (Strep) 
or Staphylococcal 
(Staph) infections) 
 
 
 
 
 
      
      
      
      
      
      
      
      
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Condition 
Yes/No/Unk Start 
date 
Stop 
date 
Ongoing 
(Yes/No) 
Details, including treatments received 
Viral Infections in the 
last 6 months (COVID-
19, Influenza (Flu), 
Parvovirus, 
Enterovirus 
(Cocksackie virus), 
etc.) 
 
 
 
 
 
Viral Infections in the 
last 6 months (COVID-
19, Influenza (Flu), 
Parvovirus, 
Enterovirus 
(Cocksackie virus), 
etc.) 
 
 
 
 
 
Fungal Infections in 
the last 6 months (e.g., 
yeast infections 
(Candida), Aspergillus, 
Histoplasma, etc.) 
 
 
 
 
 
Tick-borne disease 
(Lyme disease, 
Ehrlichiosis, 
Babesiosis, etc.) 
 
 
 
 
 
Autoimmune disorders 
(e.g., systemic lupus 
erythematosus (SLE), 
Sjogren’s syndrome, 
giant cell arteritis, 
rheumatoid arthritis, 
mixed connective 
tissue disease, 
rheumatic fever, etc.) 
 
 
 
 
 
HIV 
 
 
 
 
 
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Condition 
Yes/No/Unk Start 
date 
Stop 
date 
Ongoing 
(Yes/No) 
Details, including treatments received 
Use of 
Immunosuppressant 
medications 
 
 
 
 
 
Cancer 
 
 
 
 
 
Radiation and/or 
Chemotherapy 
treatment 
 
 
 
 
 
Additional Medications (including concomitant medications). If space is not sufficient, please include a printout of the 
patient’s medications.  
Drug Name 
Indication 
Dose and 
Frequency 
Start Date 
Stop Date 
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
 
 
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Additional Event Information 
In your opinion, what is the causal 
relationship between the 
inflammatory cardiac adverse 
event and the ABNCoV2 
vaccination? 
  Related      
  Not Related 
If not related, what was the cause of the inflammatory cardiac adverse event?       
In your opinion, what is the causal 
relationship between the 
inflammatory cardiac adverse 
event and the Comirnaty 
vaccination? 
  Related      
  Not Related 
If not related, what was the cause of the inflammatory cardiac adverse event?       
Were alternate causes for the 
signs and symptoms ruled out? 
Yes 
No 
If yes, please describe how these were ruled out:       
 
Please provide any additional, relevant information on a separate page. 
Signature of person completing form:         
Date Completed:        
Name and function of person completing form (Print):        
 
Email:        
Phone:        
 
 
 
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Appendix 5: Signature Page 
Investigator Signature Page 
Herewith I agree that I have read and fully understand this protocol: 
Evaluation of the Immunogenicity, Safety and Tolerability of a Single Dose of ABNCoV2 
Vaccine in Adult Subjects Previously Vaccinated for SARS-CoV-2: a Phase 3 Trial in Two 
Parts—Randomized, Double-blind, Active Controlled and Open-label, Single-arm 
This protocol describes necessary information to conduct the trial. I agree that I will conduct the 
trial according to the instructions given within this protocol. Furthermore, I agree that I will 
conduct this trial according to International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP), the 2013 version of the Declaration of Helsinki, as well as applicable local legal and 
regulatory requirements in the respective countries. Additionally, I will follow all applicable 
national regulations requirements (e.g., German Arzneimittelgesetz). I agree that all information 
revealed in this protocol is handled strictly confidential. 
Additionally, I will permit trial-related monitoring, audits, Institutional Review Board (IRB) / 
Independent Ethics Committee (IEC) review and regulatory inspections, providing direct access 
to source data/documents. 
 
 
 
 
 
 
 
 
(Date) 
 
(Signature) Name, MD 
 
Principal Investigator (PI) 
 
Address 
 
 
 
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Coordinating Investigator Signature Page 
Evaluation of the Immunogenicity, Safety and Tolerability of a Single Dose of ABNCoV2 
Vaccine in Adult Subjects Previously Vaccinated for SARS-CoV-2: a Phase 3 Trial in Two 
Parts—Randomized, Double-blind, Active Controlled and Open-label, Single-arm 
I agree that the protocol was written according to international ethical and scientific quality 
standards (ICH GCP), in compliance with the 2013 version of the Declaration of Helsinki and 
local legal and regulatory requirements applicable in the respective country. 
 
 
 
 
 
 
 
 
 
 
 
 
(Date) 
 
(Signature)  [Name, Department] 
 
Coordinating Investigator 
 
Address 
 
 
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Sponsor Signature Page
Evaluation of the Immunogenicity, Safety and Tolerability of a Single Dose of ABNCoV2 
Vaccine in Adult Subjects Previously Vaccinated for SARS-CoV-2: a Phase 3 Trial in Two 
Parts—Randomized, Double-blind, Active Controlled and Open-label, Single-arm
By signing the protocol:
the undersigned parties agree that the protocol was written according to international ethical and 
scientific quality standards (ICH GCP), in compliance with the 2013 version of the Declaration of 
Helsinki and local legal and regulatory requirements applicable in the respective country.
Coordinating Author
and Medical Monitor
Biostatistician
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Appendix 6: Summary of Changes for Amendment#1 
to the Clinical Trial Protocol  
A Randomized, Active Controlled Phase 3 Trial to Evaluate the Immunogenicity, Safety, 
and Tolerability of a Single Boost Dose of ABNCoV2 Vaccine in Adult Subjects Previously 
Vaccinated for SARS-CoV-2 
Date of Edition 2.0: 01-Apr-2022 
Rationale 
The protocol Edition 2.0 has been created to implement corrections to the previous edition. 
Changes 
Changes/added terms are highlighted in bold letters in the text (see Table 5 below), deleted terms 
are marked using strikethrough. 
Table 5 
Description of Changes from Edition 1.0 to Edition 2.0 
Clinical Trial Protocol Edition 1.0,  
dated 28-Feb-2022  
Previously written: 
Clinical Trial Protocol Edition 2.0,  
dated 01-Apr-2022  
Changed to: 
1.3 Trial Synopsis 
Trial Design (page 11) 
This phase 3 trial will compare vaccination with a 
single dose of 100 g ABNCoV2 to a single 
standard adult dose of Comirnaty in previously 
vaccinated adult subjects who are eligible to 
receive a boost or re-boost (applies to Cohort 3 
only) vaccination according to local guidelines, 
and whose last authorized SARS-CoV-2 
vaccination is at least 3 months (Cohorts 2 and 3) 
or 6 months (Cohort 1) prior to the screening visit. 
1.3 Trial Synopsis 
Trial Design (page 11) 
This phase 3 trial will compare vaccination with a 
single dose of 100 g ABNCoV2 to a single 
standard adult dose of Comirnaty in previously 
vaccinated adult subjects who are eligible to 
receive a boost or re-boost (applies to Cohort 3 
only) vaccination, and whose last authorized 
SARS-CoV-2 vaccination is at least 3 months 
(Cohorts 2 and 3) or 6 months (Cohort 1) prior to 
the screening visit. Where local guidelines are 
available, subjects should be eligible for boost 
or re-boost vaccination according to those 
guidelines. 
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Clinical Trial Protocol Edition 1.0,  
dated 28-Feb-2022  
Previously written: 
Clinical Trial Protocol Edition 2.0,  
dated 01-Apr-2022  
Changed to: 
1.3 Trial Synopsis 
Sample Size (page 12) 
x 
Cohort 1: subjects who previously completed 
a primary vaccination regimen with 
Comirnaty at least 6 months prior to the 
screening visit and in accordance with local 
guidelines regarding vaccine eligibility 
x 
Cohort 2: subjects who previously completed 
a primary vaccination regimen with 
authorized SARS-CoV-2 vaccines (defined in 
Section 1.2) at least 3 months prior to the 
screening visit and in accordance with local 
guidelines regarding vaccine eligibility; this 
includes subjects who completed a primary 
Comirnaty regimen at least 3 months but less 
than 6 months before the screening visit 
x 
Cohort 3: subjects who have received at least 
1 booster vaccination with an authorized 
SARS-CoV-2 vaccine (defined in Section 1.2) 
at least 3 months prior to the screening visit 
and in accordance with local guidelines 
regarding booster eligibility 
1.3 Trial Synopsis 
Sample Size (page 12) 
x 
Cohort 1: subjects who previously completed a 
primary vaccination regimen with Comirnaty 
at least 6 months prior to the screening visit 
x 
Cohort 2: subjects who previously completed a 
primary vaccination regimen with authorized 
SARS-CoV-2 vaccines (defined in Section 
1.2) at least 3 months prior to the screening 
visit; this includes subjects who completed a 
primary Comirnaty regimen at least 3 months 
but less than 6 months before the screening 
visit 
x 
Cohort 3: subjects who have received at least 1 
booster vaccination with an authorized 
SARS-CoV-2 vaccine (defined in Section 1.2) 
at least 3 months prior to the screening visit 
1.4 Trial Schedule 
1.4 Trial Schedule 
Demographics collection row added, X added in 
SCR column 
2.2.2 Clinical Trials with ABNCoV2 Vaccine 
Table 1 Overall Summary of Adverse Events in 
Seropositive Subjects During the Active Trial 
Period 
Row 6: Solicited general AEs, related 
2.2.2 Clinical Trials with ABNCoV2 Vaccine 
Table 1 Overall Summary of Adverse Events in 
Seropositive Subjects During the Active Trial 
Period 
Row 6: Solicited general AEs 
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Clinical Trial Protocol Edition 1.0,  
dated 28-Feb-2022  
Previously written: 
Clinical Trial Protocol Edition 2.0,  
dated 01-Apr-2022  
Changed to: 
3 Trial Design 
This is a randomized, active controlled phase 3 
trial to compare vaccination with a single dose of 
100 g ABNCoV2 to a single standard adult dose 
of Comirnaty in adult subjects previously 
vaccinated for SARS-CoV-2 who are eligible to 
receive a boost vaccination according to local 
guidelines. 
… 
x 
Cohort 1: approximately 625 to 1000 
subjects with a previously completed 
primary vaccination regimen with 
Comirnaty (Pfizer/BioNTech SARS-CoV-2 
vaccine) at least 6 months prior to the 
screening visit and in accordance with local 
guidelines regarding vaccine eligibility 
x 
Cohort 2: subjects who previously 
completed a primary vaccination regimen 
with authorized SARS-CoV-2 vaccines 
(e.g., 2 doses of Spikevax, 1 dose of 
Janssen, 2 doses of Vaxzevria, or any mix-
and-match vaccinations) at least 3 months 
prior to the screening visit and in 
accordance with local guidelines regarding 
vaccine eligibility; this includes subjects 
who completed a primary Comirnaty 
vaccination regimen at least 3 months but 
less than 6 months before the screening 
visit  
x 
Cohort 3: subjects who have received at 
least 1 booster vaccination with an 
authorized SARS-CoV-2 booster vaccine at 
least 3 months prior to the screening visit 
and in accordance with local guidelines 
regarding booster eligibility 
3 Trial Design 
This is a randomized, active controlled 
phase 3 trial to compare vaccination with a 
single dose of 100 g ABNCoV2 to a single 
standard adult dose of Comirnaty in adult 
subjects previously vaccinated for 
SARS-CoV-2. Where local guidelines are 
available, subjects should be eligible to 
receive a boost or re-boost vaccination 
according to those guidelines. 
… 
x 
Cohort 1: approximately 625 to 1000 
subjects with a previously completed 
primary vaccination regimen with 
Comirnaty (Pfizer/BioNTech 
SARS-CoV-2 vaccine) at least 6 months 
prior to the screening visit  
x 
Cohort 2: subjects who previously 
completed a primary vaccination 
regimen with authorized SARS-CoV-2 
vaccines (e.g., 2 doses of Spikevax, 1 
dose of Janssen, 2 doses of Vaxzevria, 
or any mix-and-match vaccinations) at 
least 3 months prior to the screening 
visit; this includes subjects who 
completed a primary Comirnaty 
vaccination regimen at least 3 months 
but less than 6 months before the 
screening visit  
x 
Cohort 3: subjects who have received at 
least 1 booster vaccination with an 
authorized SARS-CoV-2 booster 
vaccine at least 3 months prior to the 
screening visit 
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Clinical Trial Protocol Edition 1.0,  
dated 28-Feb-2022  
Previously written: 
Clinical Trial Protocol Edition 2.0,  
dated 01-Apr-2022  
Changed to: 
9.1 Production, Packaging and Labeling 
The packages and vials of ABNCoV2 vaccine 
are labeled according to regulatory 
requirements. Vials contain at least 100 g in 
0.3 mL.  
9.1 Production, Packaging and Labeling 
The packages and vials of ABNCoV2 vaccine are 
labeled according to regulatory requirements. 
Vials contain at least 100 g in 0.5 mL. 
 
 
 
 
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Appendix 7: Summary of Changes for Amendment#2 
to the Clinical Trial Protocol  
Evaluation of the Immunogenicity, Safety, and Tolerability of a Single Dose of ABNCoV2 
Vaccine in Adult Subjects Previously Vaccinated for SARS-CoV-2: a Phase 3 Trial in Two 
Parts—Randomized, Double-blind, Active Controlled and Open-label, Single-arm 
Date of Edition 3.0: 01-Jun-2022 
Rationale 
The protocol Edition 3.0 has been created to implement a title change and major design changes 
to the previous edition. 
Changes 
Changes are extensive and throughout the document. They are summarized at a high level below 
in Table 6. 
Table 6 
Description of Changes from Edition 2.0 to Edition 3.0 
Change 
Trial is to be conducted in two parts: 
x Part A: randomized, double-blind component 
x Part B: single-arm, open-label component 
Cohorts in each part to be subjects who have received primary vaccination only (Cohort 1) and 
subjects who have received primary plus 1 booster vaccination (Cohort 2) 
Source of comparator vaccine changed from routine access to blinded trial vaccine 
Randomization ratio changed from 3:1 to 1:1  
Single-arm component mostly for safety analyses but also includes subset for humoral and 
cellular immunogenicity 
Non-inferiority testing to be done in randomized component in both cohorts simultaneously, and if non-
inferiority margin is met, then superiority testing to be done as well in the same cohort(s) 
Comparison added between cohorts in Parts A and B 
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Change 
Enrollment of a homologous primary vaccination cohort dropped 
Number of prior booster vaccinations limited to 1 
Inclusion relaxed to prior vaccination at least 3 months before screening (reduced from 6 months) 
Exclusion limited to COVID-19 infection in last 3 months (reduced from 6 months) 
Trial population to include 1000 subjects 65 years of age 
Trial schedule: Visit 1 and day of vaccination combined (no need to allow time for routine access) 
Safety data updated to be consistent with Topline Interim Clinical Study Report 
T-cell data added to phase 2 results in Background section 
Gate-keeping approach to multiplicity described 
Seropositivity (2-fold and 4-fold increase) added as supportive analyses 
Unblinding process added 
COVID-19 resulting in critical illness added to severe COVID-19 as cases to be reviewed by DMC 
Sites limited to Belgium, Denmark, and US 
Clinical trial identifiers added 
Editorial changes made for clarity and accuracy throughout 
 
 
 
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Appendix 8: Summary of Changes for Amendment#3 
to the Clinical Trial Protocol  
Evaluation of the Immunogenicity, Safety, and Tolerability of a Single Dose of ABNCoV2 
Vaccine in Adult Subjects Previously Vaccinated for SARS-CoV-2: a Phase 3 Trial in Two 
Parts—Randomized, Double-blind, Active Controlled and Open-label, Single-arm 
Date of Edition 4.0: 09-Jun-2022 
Rationale 
The protocol Edition 4.0 has been created to implement changes to the previous edition. 
Changes 
Changes/ added terms are highlighted in bold letters in the text (see Table 7 below), deleted 
terms are marked using strikethrough. 
Table 7 
Description of Changes from Edition 3.0 to Edition 4.0 
Clinical Trial Protocol Edition 3.0,  
dated 01-Jun-2022  
Previously written: 
Clinical Trial Protocol Edition 4.0,  
dated 09-Jun-2022  
Changed to: 
1.3 Trial Synopsis 
Exclusion Criteria 
9. Laboratory parameters (such as complete blood 
count, serum biochemistry including aspartate 
aminotransferase [AST], alanine amino 
transferase [ALT], alkaline phosphokinase 
[ALP], bilirubin, or creatinine values), pulse 
rate, blood pressure, or electrocardiogram 
(ECG) outside normal range at screening and 
deemed clinically relevant by the investigator. 
1.3 Trial Synopsis 
Exclusion Criteria 
9. Laboratory parameters (such as complete blood 
count, serum biochemistry including aspartate 
aminotransferase [AST], alanine amino 
transferase [ALT], alkaline phosphokinase 
[ALP], bilirubin, or creatinine values), pulse 
rate, or blood pressure outside normal range at 
screening and deemed clinically relevant by the 
investigator. 
1.4 Trial Schedule 
ECG row, X in SCR column 
Abbreviations:…ECG = electrocardiogram 
1.4 Trial Schedule 
ECG row deleted, abbreviation deleted 
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Clinical Trial Protocol Edition 3.0,  
dated 01-Jun-2022  
Previously written: 
Clinical Trial Protocol Edition 4.0,  
dated 09-Jun-2022  
Changed to: 
8.4 Unscheduled Visit 
Clinically indicated additional visits may be 
necessary between scheduled visits. 
Unscheduled visits may be performed, e.g., to 
repeat laboratory testing or physical exams 
due to a new development. Examinations 
performed at unscheduled visits will be 
recorded in the source documents as well as in 
the respective eCRF sections for unscheduled 
visits. 
8.4 Unscheduled Visit 
Clinically indicated additional procedures or 
visits may be necessary at any time, including 
between scheduled visits. Unscheduled visits may 
be performed, e.g., to repeat laboratory testing or 
physical exams due to a new development or to 
perform any clinically indicated evaluation, 
such as an electrocardiogram (ECG). 
Examinations performed at unscheduled visits will 
be recorded in the source documents as well as in 
the respective eCRF sections for unscheduled 
visits. 
Appendix 3: Interpretation Support for 
Assessment of Screening ECGs 
Appendix deleted in its entirety. 
 
 
 
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Appendix 9: Summary of Changes for Amendment#4 
to the Clinical Trial Protocol 
Evaluation of the Immunogenicity, Safety, and Tolerability of a Single Dose of ABNCoV2 
Vaccine in Adult Subjects Previously Vaccinated for SARS-CoV-2: a Phase 3 Trial in Two 
Parts—Randomized, Double-blind, Active Controlled and Open-label, Single-arm 
Date of Edition 5.0: 14-Jun-2022 
Rationale 
The protocol Edition 5.0 has been created to implement administrative corrections to the previous 
edition. 
Changes 
Page breaks were added to keep the appendices on separate pages. 
 
 
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Appendix 10: Summary of Changes for Amendment#5 
to the Clinical Trial Protocol 
Evaluation of the Immunogenicity, Safety, and Tolerability of a Single Dose of ABNCoV2 
Vaccine in Adult Subjects Previously Vaccinated for SARS-CoV-2: a Phase 3 Trial in Two 
Parts—Randomized, Double-blind, Active Controlled and Open-label, Single-arm 
Date of Edition 6.0: 28-Jul-2022 
Rationale 
The protocol Edition 6.0 has been created to implement changes to the previous edition as 
requested by FDA. 
Changes 
Changes/added terms are highlighted in bold letters in the text (see Table 8 below), deleted terms 
are marked using strikethrough. 
Table 8 
Description of Changes from Edition 5.0 to Edition 6.0 
Clinical Trial Protocol Edition 5.0,  
dated 09-Jun-2022  
Previously written: 
Clinical Trial Protocol Edition 6.0,  
dated 28-Jul-2022  
Changed to: 
1.1 Abbreviations 
 
1.1 Abbreviations 
MAAE medically attended adverse event 
12.10 Trial Synopsis 
Safety Endpoint Population-level Summaries 
Part A: For all subjects receiving ABNCoV2 
compared to those receiving Comirnaty, the 
percent who report the below: 
Parts A and B: For all subjects receiving 
ABNCoV2, the percent who report the below: 
x Any serious adverse events (SAEs) or 
adverse events of special interest (AESIs) 
assessed as related to trial vaccine during 
the trial period. 
x Any Grade 3 or higher adverse events 
(AEs) assessed as related to trial vaccine 
in the 8-day period starting with the day of 
vaccination.  
x Any SAE or AESI, regardless of 
relationship, during the active trial phase. 
12.10 Trial Synopsis 
Safety Endpoint Population-level Summaries 
Part A: For all subjects receiving ABNCoV2 
compared to those receiving Comirnaty, the 
percent who report the safety endpoints listed 
below. 
Parts A and B: For all subjects receiving 
ABNCoV2, the percent who report the safety 
endpoints listed below. 
 
Safety endpoints: 
x Serious adverse events (SAEs) or adverse 
events of special interest (AESIs) assessed 
as related to trial vaccine during the entire 
trial period, which includes both the 
active trial phase and follow-up. 
x Grade 3 or higher adverse events (AEs) 
assessed as related to trial vaccine in the 
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Previously written: 
Clinical Trial Protocol Edition 6.0,  
dated 28-Jul-2022  
Changed to: 
x Any SAEs or AESIs, regardless of 
relationship, during the entire trial period. 
x Any Grade 3 or higher AEs assessed as 
related to trial vaccine during the active 
trial phase. 
x Solicited local AEs in the 8-day period 
starting with the day of vaccination. 
x Solicited general AEs in the 8-day period 
starting with the day of vaccination. 
 
8-day period starting with the day of 
vaccination.  
x SAEs, AESIs, or medically attended AEs 
(MAAEs), regardless of relationship, 
during the active trial phase. 
x SAEs, AESIs, or MAAEs, regardless of 
relationship, during the entire trial period. 
x Grade 3 or higher AEs assessed as related 
to trial vaccine during the active trial 
phase. 
x Solicited local AEs in the 8-day period 
starting with the day of vaccination. 
x Solicited general AEs in the 8-day period 
starting with the day of vaccination. 
12.10 Trial Synopsis 
Trial Population: Exclusion Criteria 
 
12.10 Trial Synopsis 
Trial Population: Exclusion Criteria 
6. History of myocarditis or pericarditis. 
(added, other subsequent criteria renumbered) 
1.4 Trial Schedule 
 
1.4 Trial Schedule 
ECGb (added at Screening) 
AE/SAE/AESI/MAAE recording 
Abbreviations:… MAAE = medically attended 
adverse event; 
g AESIs and MAAEs are not collected until vaccine 
has been received at visit 1. 
h During the follow-up period, data collection will be 
limited to SAEs, AESIs, and MAAEs, and any 
unsolicited AEs from the active trial period that are 
not yet resolved. 
2.4.1 Risks 
2.4.1 Risks 
Myocarditis and pericarditis have so far not 
been observed in the phase 1 and phase 2 
clinical development program of ABNCoV2. 
However, available data regarding myocarditis 
or pericarditis reported in individuals 
vaccinated with some licensed COVID-19 
vaccines containing the S antigen strongly 
support a plausible causal relationship to the 
vaccines and have warranted inclusion of a 
warning statement and additional safety 
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Clinical Trial Protocol Edition 5.0,  
dated 09-Jun-2022  
Previously written: 
Clinical Trial Protocol Edition 6.0,  
dated 28-Jul-2022  
Changed to: 
information about these events in EUA Fact 
Sheets and labeling of those approved vaccines. 
5.3 Safety Endpoints 
The endpoints include the frequency and 
percentage of subjects who report the 
following: 
x SAEs or adverse events of special interest 
(AESIs) assessed as related to trial vaccine 
during the trial period, which includes 
both the active trial phase and follow-up. 
x Grade 3 or higher adverse events (AEs) 
assessed as related to trial vaccine in the 
8-day period starting with the day of 
vaccination. 
x SAEs or AESIs, regardless of relationship, 
during the active trial phase. 
x SAEs or AESIs, regardless of relationship, 
during the entire trial period (active trial 
phase and follow-up). 
x Grade 3 or higher AEs assessed as related 
to trial vaccine during the active trial 
phase. 
x Solicited local AEs in the 8-day period 
starting with the day of vaccination. 
x Solicited general AEs in the 8-day period 
starting with the day of vaccination. 
 
5.3 Safety Endpoints 
The endpoints include the frequency and 
percentage of subjects who report the 
following: 
x SAEs or adverse events of special interest 
(AESIs) assessed as related to trial vaccine 
during the entire trial period, which 
includes both the active trial phase and 
follow-up. 
x Grade 3 or higher adverse events (AEs) 
assessed as related to trial vaccine in the 
8-day period starting with the day of 
vaccination. 
x SAEs, AESIs, or medically attended AEs 
(MAAEs), regardless of relationship, 
during the active trial phase. 
x SAEs, AESIs, or MAAEs, regardless of 
relationship, during the entire trial. 
x Medically attended AEs (MAAEs), 
regardless of relationship, during the 
active trial phase. 
x MAAEs assessed as related to trial 
vaccine during the entire trial period. 
x Grade 3 or higher AEs assessed as related 
to trial vaccine during the active trial 
phase. 
x Solicited local AEs in the 8-day period 
starting with the day of vaccination. 
x Solicited general AEs in the 8-day period 
starting with the day of vaccination. 
8.3 Follow-up Phase 
… the core procedures from the active phase are 
repeated, including collection of AESIs and 
SAEs… 
8.3 Follow-up Phase 
… the core procedures from the active phase are 
repeated, including collection of MAAEs, AESIs, 
and SAEs… 
9.1 Production, Packaging and Labeling 
 
9.1 Production, Packaging and Labeling 
Link to US prescribing information for Comirnaty 
updated 
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Clinical Trial Protocol Edition 5.0,  
dated 09-Jun-2022  
Previously written: 
Clinical Trial Protocol Edition 6.0,  
dated 28-Jul-2022  
Changed to: 
9.2 Shipment, Storage, and Handling 
ABNCoV2 and Comirnaty vaccines are shipped 
and stored at -20°C (±5°C).  
9.2 Shipment, Storage, and Handling 
ABNCoV2 vaccine is shipped and stored at -20°C 
(±5°C). Comirnaty vaccine is shipped and 
stored according to package leaflet 
instructions. For further details see the 
pharmacy manual. 
11 Safety and Reactogenicity 
Safety will be monitored in both Part A and Part B 
by collection of medical history at baseline… 
11 Safety and Reactogenicity 
Safety will be monitored in both Part A and Part B 
by collection of medical history and performance 
of an electrocardiogram (ECG) at baseline… 
11.1.5 SAEs and AESIs 
11.1.5 SAEs, AESIs, and MAAEs 
 
MAAEs are defined as adverse events with 
medically attended visits that were not 
routine visits for physical examination or 
vaccination, such as visits for 
hospitalization, an emergency room visit, 
or an otherwise unscheduled visit to or 
from medical personnel (medical doctor) 
for any reason. 
11.7 Unsolicited AEs 
SAEs and AESIs will be collected throughout the 
entire trial… 
11.7 Unsolicited AEs 
SAEs, AESIs, and MAAEs will be collected 
throughout the entire trial… 
11.9 Adverse Events of Special Interest 
11.9 Adverse Events of Special Interest 
11.9.1 General AESI Definitions 
…For timelines for reporting and follow-up 
of AESIs, see section 11.13.1. The same 
timelines and reporting processes as for 
SAEs are applicable. 
11.9 Adverse Events of Special Interest 
 
11.9 Adverse Events of Special Interest 
11.9.2 Myocarditis and Pericarditis (entire 
section was added) 
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Clinical Trial Protocol Edition 5.0,  
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Previously written: 
Clinical Trial Protocol Edition 6.0,  
dated 28-Jul-2022  
Changed to: 
11.12 Cardiac Assessment 
11.12 Cardiac Assessment 
A standard 12-lead ECG will be required at 
screening. An ECG may be performed at any 
other visit if clinically indicated. The 
investigator will assess the clinical significance 
for abnormal ECGs. (section added, subsequent 
sections renumbered) 
11.14 Reporting 
11.14 Reporting 
11.14.2 Reporting of MAAEs  
All MAAEs will be collected for the trial 
duration, including the follow-up period. 
MAAEs must be entered in the eCRF within 
24 hours of awareness by the investigators. If 
an MAAE is considered serious or meets 
criteria for an AESI, reporting procedures in 
Section 11.14.1 are to be followed. 
(section was added, subsequent section 
renumbered) 
13.3.2 Stopping Rules 
13.3.2 Stopping Rules 
… 
x Any case of myocarditis or pericarditis 
in temporal association to the 
administration of trial vaccine 
…  
A DMC meeting should be convened within 
48 hours after the sponsor receives the 
relevant safety information. 
Appendix 3 
Appendix 3: Myocarditis and Pericarditis 
Scale, Brighton Collaboration 
Table 4 Myocarditis Case Definition for 
Surveillance of Adverse Events after 
Vaccination  
(appendix and table added, subsequent appendices 
renumbered) 
Appendix 4 
Appendix 4: Adverse Event Follow-up 
Questionnaire — Inflammatory Cardiac 
Disorders (appendix added, subsequent 
appendices renumbered) 
 
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Appendix 11: Summary of Changes for Amendment#6 
to the Clinical Trial Protocol 
Evaluation of the Immunogenicity, Safety, and Tolerability of a Single Dose of ABNCoV2 
Vaccine in Adult Subjects Previously Vaccinated for SARS-CoV-2: a Phase 3 Trial in Two 
Parts—Randomized, Double-blind, Active Controlled and Open-label, Single-arm 
Date of Edition 7.0: 15-Feb-2023 
Rationale 
The protocol Edition 7.0 has been created to implement changes to the previous edition as 
requested by EMA. 
Changes 
Changes/added terms are highlighted in bold letters in the text (see Table 9 below), deleted terms 
are marked using strikethrough. 
Table 9 
Description of Changes from Edition 6.0 to Edition 7.0 
Clinical Trial Protocol Edition 6.0,  
dated 28-Jul-2022  
Previously written: 
Clinical Trial Protocol Edition 7.0,  
dated 15-Feb-2023 
Changed to: 
1.1 Abbreviations 
1.1 Abbreviations 
(added) SAR: serious adverse reaction 
1.2 Definitions 
x 
“completed vaccination regimen” defined as: 
Completed vaccination regimen with a locally 
authorized SARS-CoV-2 vaccine. 
“Completed” includes full primary 
vaccination as described in the labeling of the 
initial vaccine, but also includes any 
mix/match series of 2 doses… 
1.2 Definitions 
“completed primary vaccination regimen” 
defined as: 
Completed primary vaccination regimen with 
a locally authorized SARS-CoV-2 vaccine. 
“Completed primary vaccination regimen” 
includes full primary vaccination as described 
in the labeling of the initial vaccine, with no 
less than 3 weeks between the doses; 
completed primary vaccination also includes 
any mix/match series of 2 doses… 
“completed primary plus boost vaccination” 
added: 
Completed primary plus boost vaccination 
with locally authorized SARS-CoV-2 
vaccine(s). “Completed primary plus boost 
vaccination” includes full primary 
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Clinical Trial Protocol Edition 6.0,  
dated 28-Jul-2022  
Previously written: 
Clinical Trial Protocol Edition 7.0,  
dated 15-Feb-2023 
Changed to: 
vaccination as described above plus a boost 
vaccination administered at least 2 months 
after the last primary dose. The boost dose 
may be the same or different vaccine as 
received in the primary vaccination 
regimen. 
“end of study/study completion” added: 
The final date on which data are collected 
(i.e., the last subject’s last visit or scheduled 
assessment). 
1.3 Protocol Synopsis, Sites and Countries 
Part A: X sites in Belgium and Denmark 
Part B: Y sites in the United States and Denmark  
1.3 Protocol Synopsis, Sites and Countries 
Part A: 13 sites in Belgium and Denmark 
Part B: 45 sites in the United States 
1.3 Protocol Synopsis, Sample Size 
The immunogenicity subset in Part B will consist 
of approximately 250 subjects in each cohort. This 
subset sample size is based on feasibility alone. 
1.3 Protocol Synopsis, Sample Size 
The immunogenicity subset in Part B will consist 
of approximately 200 to 250 subjects in each 
cohort. This subset sample size is based on 
feasibility alone, i.e., the number of 
participating sites and consenting subjects. 
1.3 Protocol Synopsis, Trial Population: 
Inclusion Criteria 
2. Documented, previous administration of 
locally authorized SARS-CoV-2 vaccine(s) 
for primary vaccination only or for primary 
plus 1 boost vaccination, with last vaccination 
at least 3 months before screening… 
 
 
 
 
Exclusion Criteria 
16. History of any vaccinations or plan to receive 
any vaccinations with an inactivated vaccine 
within 14 days prior to or after trial 
vaccination. 
1.3 Protocol Synopsis, Trial Population: 
Inclusion Criteria 
2. Documented, previous completion of a 
primary vaccination regimen with locally 
authorized SARS-CoV-2 vaccine(s) or 
completion of primary plus 1 boost 
vaccination (see definition of completed 
primary vaccination regimen and 
completed primary plus boost vaccination 
in Section 1.2), with last vaccination at least 
3 months before screening… 
Exclusion Criteria 
16. History of any vaccinations or plan to receive 
any vaccinations with a non-live vaccine 
within 14 days prior to or after trial 
vaccination. 
23. Known bleeding disorder that, in the 
opinion of the investigator, would 
contraindicate intramuscular injection. 
 
 
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1.4 Trial Schedule
AE/SAE/AESI/MAAE recording
Blood collection for serum antibody titers, Part A
Blood collection for serum antibody titers, Part B
immunogenicity subsetj,
1.4 Trial Schedule
AE/SAE/SAR/AESI/MAAE recording
Blood collection for serum antibody titers and 
nucleocapsid protein antibody testingi, Part A
Blood collection for serum antibody titers and 
nucleocapsid protein antibody testing, Part B
immunogenicity subsetk
(added abbreviation) SAR = serious adverse 
reaction
(added footnote, subsequent footnote lettering 
changed)
i Nucleocapsid protein antibody testing will be done
only on samples collected at V1 and V3.
1.5 Responsibilities
Project Leader
Medical Monitor
Trial Statistician
1.5 Responsibilities
Project Leader
Medical Monitor (
)
Medical Monitor (BN)
Trial Statistician
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3.2 Trial Design, Part B
Additionally, a subset of sites in the US will 
collect blood for serum and peripheral blood 
mononuclear cells (PBMCs) from approximately 
500 subjects (250 from each cohort).
3.2 Trial Design, Part B
Additionally, a subset of sites in the US will 
collect blood for serum and peripheral blood 
mononuclear cells (PBMCs) from approximately 
500 subjects (200 to 250 from each cohort).
3.3 End of Study / Study Completion (added)
Study completion is defined as the final date on 
which data are collected (i.e., the last subject’s 
last visit or scheduled assessment).
6.3 Inclusion of Older Subjects
Sites will be instructed to pursue a target of at 
least 25% of enrollment to be subjects that are 
65 years of age for Part A and at least 33% to be 
65 years of age for Part B.
6.3 Inclusion of Older Subjects
Sites will be instructed to pursue a target of 25% 
of enrollment to be subjects that are 65 years of 
age for Part A and 33% to be 65 years of age for 
Part B.
8.2.1 Visit 1
…of greatest importance is that collection of 
immunogenicity samples must always be 
performed prior to vaccine administration.
8.2.1 Visit 1
…of greatest importance is that collection of 
samples for serum antibody titers, PBMC 
testing, and nucleocapsid protein antibody 
testing must always be performed prior to vaccine 
administration.
8.2.3 Visit 3
…and for serum antibody titers in Part A…
8.2.3 Visit 3
…and for serum antibody titers and nucleocapsid 
protein antibody testing in Part A
8.4 Unscheduled Visit
Unscheduled visits may be performed, e.g., to 
repeat laboratory testing or physical exams due to 
a new development, or to perform any clinically 
indicated evaluation,…
8.4 Unscheduled Visit
Unscheduled visits may be performed, e.g., to 
repeat laboratory testing or physical exams due to 
a new development, to do PCR testing for 
suspected COVID-19 infection, or to perform 
any clinically indicated evaluation,…
10.3 Nucleocapsid Protein Antibody Testing
(added, subsequent section renumbered)
Serum samples also will be used to analyze 
nucleocapsid protein antibody titers as outlined 
in the trial procedure schedule in Section 1.4
(at Visits 1 and 3) in Part A and at selected 
investigational sites participating in the Part B
immunogenicity subset. Samples for 
nucleocapsid protein antibody testing obtained 
at Visit 1 will be drawn prior to vaccination.
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11.1.5 SAEs, SARs, AESIs, and MAAEs 
An SAE is any untoward medical occurrence 
that: 
11.1.5 Serious Adverse Events, Serious Adverse 
Reactions, Adverse Events of Special Interest, 
and Medically Attended Adverse Events 
An SAE is any untoward medical occurrence or 
effect in a subject administered the trial 
vaccine that may or may not have a causal 
relationship with the study vaccine and that is 
serious, meaning that it: (list follows) 
Though SAEs, as specified above, include all 
serious events independent of whether they 
have a suspected causal relationship to the IMP 
or not, serious adverse reactions (SARs) are 
defined as a subset of SAEs that include all 
noxious and unintended responses to the IMP 
related to any dose administered that at any 
dose results in any of the serious outcomes 
listed above. 
11.4 Prohibited Medications 
x Vaccination with any licensed live vaccine 
within 30 days prior to or after trial 
vaccination or any licensed inactivated or 
other non-replicating vaccine within 14 days 
prior to or after trial vaccination. 
11.4 Prohibited Medications 
x 
Vaccination with any licensed live vaccine 
within 30 days prior to or after trial 
vaccination or any licensed non-live vaccine 
within 14 days prior to or after trial 
vaccination. 
11.8.1 Solicited Local AEs 
Injection site erythema, swelling, and induration 
will be assessed based on the longest diameter as 
measured by the subject in mm and recorded in 
the memory aid. Subjects are asked to document 
the solicited local AEs in the memory aid as 
described in Table 2 below. 
 
 
 
 
 
 
Table 2 Grading of Local Symptoms 
 
11.8.1 Solicited Local AEs 
Injection site erythema, swelling, and induration 
will be assessed based on the longest diameter as 
measured by the subject in mm and recorded in 
the memory aid. Subjects are asked to document 
the solicited local AEs in the memory aid. For 
injection site erythema, injection site swelling, 
and injection site induration, subjects are 
asked to record longest diameters; for injection 
site pruritus and injection site pain, subjects 
are asked to record level of severity as described 
in Table 2 below. 
 
Table 2 Grading of Local Symptoms 
“Grading for Analysis” column added, with 
footnotes referencing FDA guidance 
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11.8.2 Solicited General AEs
Subjects are asked to document the solicited 
general AEs in the memory aid as described in 
Table 3 below.
Table 3 Grading of General Symptoms
11.8.2 Solicited General AEs
Subjects are asked to document the solicited 
general AEs in the memory aid. Subjects are 
asked to record temperature and severity of 
symptoms as described in Table 3 below.
Table 3 Grading of General Symptoms
“Grading for Analysis” column added, with 
footnotes referencing FDA guidance on grading of
fever
11.9.1 General AESI Definitions
For timelines for reporting and follow-up of 
AESIs, see Section 11.13.1.
11.9.1 General AESI Definitions
… Links to the Brighton Collaboration’s case 
definitions for AESIs applicable for COVID-19
vaccine trials are provided in Appendix 3.
For timelines for reporting and follow-up of 
AESIs, see Section11.14.1.
11.9.2 Myocarditis and Pericarditis
These definitions are provided in Appendix 3.
11.9.2 Myocarditis and Pericarditis
Reference to the publication of these case
definitions is provided in Appendix 3.
11.13 Pregnancyx
…(see Section 11.13.2).
11.13 Pregnancy
…(see Section 11.14.3).
11.14.2 Reporting of MAAEs
… reporting procedures in Section 11.13.1 are to 
be followed.
11.14.2 Reporting of MAAEs
… reporting procedures in Section 11.14.1 are to 
be followed.
11.14.3 Reporting of Pregnancies
… this must be reported to 
 within 24 hours 
of the investigator becoming aware of the event 
(Section 11.12).
Any event during pregnancy fulfilling the criteria 
for an SAE or AESI will be reported to 
 (see 
Section 11.13.1).
11.14.3 Reporting of Pregnancies
… this must be reported to 
 within 24 hours 
of the investigator becoming aware of the event 
(Section 11.13).
Any event during pregnancy fulfilling the criteria 
for an SAE or AESI will be reported to 
(see 
Section 11.14.1).
12.2.2 Sample Size Calculation, Part B
The immunogenicity subset in Part B will consist 
of approximately 250 subjects in each cohort. This 
subset sample size is based on feasibility alone.
12.2.2 Sample Size Calculation, Part B
The immunogenicity subset in Part B will consist 
of approximately 250 subjects in each cohort. This 
subset sample size is based on feasibility alone,
i.e., the number of participating sites and 
consenting subjects.
12.3 Multiplicity
The key secondary endpoints, ratios of GMTs for 
the VOCs at 2 weeks after trial vaccination, will 
be formally tested in Part A for non-inferiority of 
12.3 Multiplicity
The key secondary endpoints, ratios of GMTs for 
the VOCs at 2 weeks after trial vaccination, will 
be formally tested in Part A for non-inferiority of 
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ABNCoV2 to Comirnaty only in the cohort(s) in 
which the primary success criterion is met. In the 
event that success criteria are met for both 
Cohort 1 and Cohort 2, VOCs will be tested 
sequentially in separate cohorts. If the numbers of 
evaluable subjects are similar in both cohorts, 
Cohort 1 will be tested first followed by Cohort 2 
if the success criterion is met in at least one VOC 
in Cohort 1. If the numbers of evaluable subjects 
are different between the 2 cohorts, VOC will be 
tested in the cohort with the higher number of 
evaluable subjects, followed by the cohort with 
the smaller number of evaluable subjects provided 
the success criterion in the previous step is met by 
at least 1 VOC. A Bonferroni adjustment will be 
used such that each VOC non-inferiority 
hypothesis will be tested at the Į =  level. For 
example, if 3 VOCs are tested, each test will be 
performed at the Į = 0.0083 level such that 
success would require the lower confidence limit 
of a 98.3% CI to be at least 0.67. 
ABNCoV2 to Comirnaty only in the cohort(s) in 
which the primary success criterion is met. If the 
primary success criterion is met in only one 
cohort, VOCs will be formally tested in that 
cohort only. A Bonferroni adjustment will be 
used such that each VOC non-inferiority 
hypothesis will be tested at the Į = 
଴.଴ଶହ
௡௨௠௕௘௥ ௢௙ ௏ை஼௦ ௧௘௦௧௘ௗ level. For example, if 3 
VOCs are tested, each test will be performed at 
the Į = 0.0083 level such that success would 
require the lower confidence limit of a 98.3% CI 
to be at least 0.67. In the event that success 
criteria are met for both Cohort 1 and 
Cohort 2, the number of tests will multiply, and 
thus non-inferiority hypothesis will be tested at 
the Į = 
૙.૙૚૛૞
࢔࢛࢓࢈ࢋ࢘ ࢕ࢌ ࢂࡻ࡯࢙ ࢚ࢋ࢙࢚ࢋࢊ level so that the 
overall type I error rate will be no more than 
5%. 
12.5 Analysis Populations 
The Immunogenicity Analysis Set for 
immunogenicity endpoints includes all subjects 
who are in the Safety Analysis Set, have at least a 
baseline and 1 post-vaccination neutralizing 
antibody titer result, and have not tested positive 
for SARS-CoV-2 infection within 2 weeks of trial 
vaccination. 
12.5 Analysis Populations 
The Immunogenicity Analysis Set for 
immunogenicity endpoints includes all subjects 
who are in the Safety Analysis Set, have at least a 
baseline and 1 post-vaccination neutralizing 
antibody titer result, have not tested positive for 
SARS-CoV-2 infection, and have not received a 
booster outside of the trial within 2 weeks of 
trial vaccination. 
12.6.1 Primary Estimand 
The following are considered intercurrent events: 
1) Development of COVID-19 symptoms 
and having a positive test for 
SARS-CoV-2 infection prior to Visit 3 (12 
to 16 days after vaccination) and 
2) Discontinuation from the trial due to AEs. 
12.6.1 Primary Estimand 
The following are considered intercurrent events: 
1) A positive test for SARS-CoV-2 infection 
prior to Visit 3 (12 to 16 days after 
vaccination), by either PCR or increase in 
nucleocapsid protein antibody titers 
indicative of infection, and 
2) Discontinuation from the trial due to AEs. 
12.6.4 Subgroup Analyses 
The primary analysis will also be repeated for the 
following subgroups: age (<65 years and 
65 years),… 
12.6.4 Subgroup Analyses 
The primary analysis will also be repeated for the 
following subgroups: prior vaccination regimen 
(per randomization strata in Section 12.1), age 
(<65 years and 65 years),… 
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12.10 Timing of Analyses
12.10.1 Follow-up and Trial Analyses
If required, a follow-up analysis may be 
performed when all subjects have completed a 
specified period of follow-up. The final analysis 
for the trial will occur once all subjects have 
completed all follow-up or have withdrawn early 
from the trial, and the database has been locked.
12.10 Timing of Analyses
12.10.1 Primary Analyses
The primary analysis for the trial will occur 
after all subjects have completed the 2 months 
of follow up. All planned immunogenicity and 
safety analyses will be performed. A data 
review meeting will take place once all data are 
entered into the database prior to database 
lock. Once the trial data are clean and any 
queries resulting from the data review meeting 
are resolved, the database will be locked and 
unblinded for the analysis. A full CSR will be 
written for this analysis.
12.10.2Final Analyses
The data collected at the 3 month and 6 month 
follow up visits will be analyzed at the end of 
the trial after the database lock. As limited 
immunogenicity and safety data are collected 
at these time points, a CSR addendum may be 
written in place of a full CSR.
Appendix 3: Myocarditis and Pericarditis 
Scale, Brighton Collaboration
(prior case definition content deleted)
Appendix 3: Case Definitions for COVID-19
Adverse Events of Special Interest, Brighton
Collaboration
(Table 4 added, providing references to AESI case 
definitions)
Appendix 5: Signature Page
Sponsor Signature Page
Appendix 5: Signature Page
Sponsor Signature Page
Appendix 10: Summary of Changes for 
Amendment#5 to the Clinical Trial Protocol
…(see Table 7 below)…
Appendix 10: Summary of Changes for 
Amendment#5 to the Clinical Trial Protocol
…(see Table 8 below)…
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Appendix 12: Summary of Changes for Amendment#7 
to the Clinical Trial Protocol
Evaluation of the Immunogenicity, Safety, and Tolerability of a Single Dose of ABNCoV2 
Vaccine in Adult Subjects Previously Vaccinated for SARS-CoV-2: a Phase 3 Trial in Two 
Parts—Randomized, Double-blind, Active Controlled and Open-label, Single-arm
Date of Edition 8.0: 30-Jun-2023
Rationale
The protocol Edition 8.0 has been created to implement changes related to the analysis of 
nucleocapsid protein results.
Changes
Changes/added terms are highlighted in bold letters in the text (see Table 10 below), deleted
terms are marked using strikethrough. Additional minor editorial corrections were made.
Table 10
Description of Changes from Edition 7.0 to Edition 8.0
Clinical Trial Protocol Edition 7.0, 
dated 15-Feb-2023
Previously written:
Clinical Trial Protocol Edition 8.0, 
dated 30-Jun-2023
Changed to:
1.1 Abbreviations
1.1 Abbreviations
CSR: clinical study report
EUA: emergency use authorization
(spelled-out and/or abbreviated usage 
added/corrected in subsequent text)
1.4 Trial Schedule
Table row “Blood collection for serum antibody 
titers and nucleocapsid protein antibody testingi,
Part A”: X at FU2, FU3
i Nucleocapsid protein antibody testing will be 
done only on samples collected at V1 and V3.
1.4 Trial Schedule
Table row “Blood collection for serum antibody 
titers and nucleocapsid protein antibody testingi,
Part A”: Xi at FU2, FU3 (footnote added)
i Nucleocapsid protein antibody testing will be 
done only on samples collected at V1, V3, FU2, 
and FU3.
1.5 Responsibilities
1.5 Responsibilities

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Clinical Trial Protocol Edition 7.0,  
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Previously written: 
Clinical Trial Protocol Edition 8.0,  
dated 30-Jun-2023 
Changed to: 
8.3 Follow-up Phase 
…but concomitant medications and other AEs are 
no longer recorded, and blood collection for serum 
antibody testing occurs only in Part A. 
8.3 Follow-up Phase 
…but concomitant medications and other AEs are 
no longer recorded, and blood collection for serum 
antibody and nucleocapsid protein testing occurs 
only in Part A. 
10.3 Nucleocapsid Protein Antibody Testing 
Serum samples also will be used to analyze 
nucleocapsid protein antibody titers as outlined in 
the trial procedure schedule in Section 1.4 (at 
Visits 1 and 3) in Part A and at selected 
investigational sites participating in the Part B 
immunogenicity subset. 
10.3 Nucleocapsid Protein Antibody Testing 
Serum samples also will be used to analyze 
nucleocapsid protein antibody titers as outlined in 
the trial procedure schedule in Section 1.4 at 
Visits 1 and 3 and Follow-up 2 and 3 in Part A 
and at Visits 1 and 3 at selected investigational 
sites participating in the Part B immunogenicity 
subset. 
12.6.1 Primary Estimand 
The following are considered intercurrent events: 
1) A positive test for SARS-CoV-2 infection 
prior to Visit 3 (12 to 16 days after 
vaccination), by either PCR or increase in 
nucleocapsid protein antibody titers 
indicative of infection, and 
12.6.1 Primary Estimand 
The following are considered intercurrent events: 
1) A positive test for SARS-CoV-2 infection 
prior to Visit 3 (12 to 16 days after 
vaccination), by PCR, and 
12.6.3 Sensitivity and Supportive Analyses 
12.6.3 Sensitivity and Supportive Analyses 
Nucleocapsid protein test results will be used to 
perform additional sensitivity analyses of the 
primary endpoint. Test results that are 
indicative of SARS-CoV-2 infection will be 
used to exclude subjects from the analysis 
population as potential additional subjects 
experiencing the intercurrent event of 
COVID-19 infection prior to the 2 week 
timepoint. 
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Clinical Trial Protocol Edition 7.0,  
dated 15-Feb-2023  
Previously written: 
Clinical Trial Protocol Edition 8.0,  
dated 30-Jun-2023 
Changed to: 
12.8 Exploratory Endpoints 
Geometric mean titers of neutralizing antibodies 
against the SARS-CoV-2 index virus and VOCs, 
along with their corresponding 95% CIs, will be 
summarized by time point and cohort for Part A to 
explore the kinetics of humoral responses over 
time. Results will be presented in both tabular and 
graphical format. 
12.8 Exploratory Endpoints 
Geometric mean titers of neutralizing antibodies 
against the SARS-CoV-2 index virus and VOCs, 
along with their corresponding 95% CIs, will be 
summarized by time point and cohort for Part A to 
explore the kinetics of humoral responses over 
time. Like for the primary analysis, COVID-19 
infection is an intercurrent event for analyses 
of later time points due to its effect on humoral 
responses. Subjects with evidence of infection 
after the 2 week peak time point therefore will 
be removed from the Immunogenicity Analysis 
Set for these exploratory kinetic analyses. That 
is, not only will subjects with AEs of COVID-19 
and positive PCR tests be removed, but 
additionally, due to the longer duration 
between follow-up visits and the possibility of 
asymptomatic COVID-19 infections, 
nucleocapsid protein testing will be used to 
remove subjects who have evidence of 
COVID-19 infection. Results will be presented in 
both tabular and graphical format. 
 
 
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