A Phase II, Open-label, Rollover Trial to Evaluate the Safety and Immunogenicity of One or Two Boosting Doses of Comirnaty or One Dose of BNT162b2s01 in BNT162-01 Trial Subjects, or Two Boosting Doses of Comirnaty in BNT162-04 Trial Subjects
Phase: PHASE2
Conditions: COVID-19, SARS-CoV-2 Infection
Sponsor: BioNTech SE

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Statement of Compliance: This trial will be conducted in according to this protocol, the ethical principles that have their 
origin in the Declaration of Helsinki, good clinical practice (GCP), and applicable regulatory requirements. 
Confidentiality Statement: The information contained in this document is the property and copyright of BioNTech SE. 
Therefore, this document is provided in confidence to the recipient. No information contained herein shall be published, 
disclosed or reproduced without prior written approval of the proprietor(s). 
 
CLINICAL TRIAL PROTOCOL 
BNT162-14 
 
Version: 
4.0 
Date: 
20 JAN 2022 
Sponsor: 
BioNTech SE 
 
 
 
 
Trial title: 
A Phase II, open-label, rollover trial to evaluate the safety and immunogenicity 
of one or two boosting doses of Comirnaty or one dose of BNT162b2s01 in 
BNT162-01 trial subjects, or two boosting doses of Comirnaty in BNT162-04 
trial subjects 
Brief title: 
A trial investigating the safety and effects of one or two additional doses of 
Comirnaty or one dose of BNT162b2s01 in BNT162-01 or BNT162-04 trial 
subjects 
Trial phase: 
Phase II 
Indication: 
Prevention of COVID-19 disease 
Vaccine: 
BNT162 RNA-lipid nanoparticle (RNA-LNP) vaccine, either Comirnaty® or 
BNT162b2s01 
Coordinating and 
Principal investigator:  
Dr. Dr. med. Armin Schultz, CRS Clinical Research Services Mannheim 
GmbH, Germany (tel.: +49 621 150450) 
Trial conducted by: 
CRS Clinical Research Services Mannheim GmbH, Germany 
Trial sites: 
Multiple sites in Germany that participated in the trials BNT162-01 or  
BNT162-04. For details of the trial sites and site personnel, see the Trial 
Master File 
Sponsor’s medical 
representative: 
Dr. Svetlana Shpyro, Director Clinical Development, BioNTech SE 
Sponsor: 
BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany 
Regulatory identifiers: 
EudraCT no.: 2021-002387-50 
Medical Monitor: 
Contact information will be provided separately 
 
Document history 
Date 
Version number 
Valid for  
First approved version * 
27 MAY 2021 
1.0 
Germany 
Approved version * (implementing Paul-Ehrlich-
Institute (PEI) feedback on version 1.0) 
12 JUL 2021 
2.0 
Germany 
Approved version * (implementing requests for 
clarifications on version 2.0) 
12 AUG 2021 
3.0 
Germany 
Approved version * 
20 JAN 2022 
4.0 
Germany 
* Approved by the sponsor 

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1 
PROTOCOL SUMMARY 
1.1 
Trial synopsis 
Trial number: BNT162-14 
Trial title 
A Phase II, open-label, rollover trial to evaluate the safety and immunogenicity of one or 
two boosting doses of Comirnaty or one dose of BNT162b2s01 in BNT162-01 trial 
subjects, or two boosting doses of Comirnaty in BNT162-04 trial subjects. 
Trial rationale 
BioNTech has developed RNA-based vaccine candidates using a platform approach that 
enables the rapid development of vaccines against emerging viral diseases, including 
SARS-CoV-2. The BNT162b platform uses modRNA. The BNT162b platform member 
BNT162b2 (Comirnaty®) has received emergency use authorization or conditional 
marketing authorization in numerous countries worldwide for the prevention of COVID-19 
disease. As demonstrated by Comirnaty, LNP-formulated RNA-based vaccines provide 
one of the most flexible, scalable and fastest approaches to provide protection against the 
emerging viruses like SARS-CoV-2 (Mulligan et al. 2020; Rauch et al. 2018; Sahin et al. 
2014; Walsh et al. 2020). 
This rollover trial (BNT162-14) will enroll BNT162-01 or BNT162-04 trial subjects; the 
BNT162-01 or BNT162-04 trials are also referred to as parent trials. The trial subjects 
represent a unique group of BNT162 vaccinees because their antibody and T-cell 
responses to SARS-CoV-2 antigens have been longitudinally characterized in the parent 
trials. Longitudinal characterization of the continuum of antibody and T-cell responses to 
BNT162 vaccines given to outbred human populations where pressure on the virus from 
genetics and evolving immune responses is simultaneously occurring, provides an 
opportunity for new and prescient insights into how the virus may evolutionarily adapt. 
Studies have demonstrated that Comirnaty protects against severe COVID-19 disease 
caused by the first generation of SARS-CoV-2 viral strains (called “L strain”, reference, or 
“wild type”) at least 6 months (unpublished data). The trial provides the opportunity to 
assess vaccine and booster induced durability of immune responses in context of more 
recent data on natural infection and cross-neutralization immunity. For example, 
SARS-CoV-2 infection and RNA vaccines such as Comirnaty induce cross-neutralization 
to multiple, more recently identified viral variants, some of which are identified as variants 
of concern (VOC) (Liu et al. 2021; Widge et al. 2021). In addition, more recent data 
suggests that natural infection will induce sustained B and T cell memory responses for at 
least six months (Dan et al. 2021; Zuo et al. 2021). 
Thus, the BNT162-14 trial proposes to evaluate the added value of booster injections of 
Comirnaty or a closely related BNT162 vaccine (BNT162b2s01 [also referred to as 
BNT162b2 (B.1.351)]), which targets the VOC strain B.1.351 originally identified in the 
Republic of South Africa. In addition, durability of immune responses will also be assessed 

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in a second group of subjects within Group B who received an alternative BNT162 vaccine 
in the BNT162-01 or BNT162-04 trial and who will be offered two injections of 30 µg 
Comirnaty as per the conditional marketing authorization as long as they have not 
received any COVID-19 vaccine independent of the parent trials. The selected subjects for 
in-depth immunologic assessments in Group B may provide additional insights (e.g., 
immuno-dominance, increasing breadth of responses to select antigens) because they 
were primed with differing antigen constructs (i.e., vaccine candidates other than 
Comirnaty) or differing doses of Comirnaty, where protection against COVID-19 disease 
was not evaluated and dosing may have been suboptimal. 
BNT162-14 will also descriptively assess if a third vaccination may improve SARS-CoV-2 
spike neutralizing antibodies in the BNT162-01 Cohort 13 transplant subjects. Based on 
published data collected from vaccinating transplant recipients with Comirnaty and data 
from the BNT162-01 trial, transplant subjects demonstrate poor neutralizing antibody 
responses to SARS-CoV-2 Spike epitopes (Boyarsky et al. 2021; Sattler et al. 2021; 
Rincon-Arevalo et al. 2021), not unexpectedly, given the known poor antibody responses 
induced by influenza vaccines in solid organ transplant patients. Safety data from 
Cohort 13 subjects in the parent trial and a 3rd and 4th vaccination of Comirnaty in healthy 
volunteers supports evaluation of three or four vaccinations in the Cohort 13 transplant 
subjects (per communication of Data Monitoring Committee reviewing trial 
BNT162-02/CA4591001 [NCT04368728], Amendment 14). While high levels of 
neutralizing antibodies elicited by viral vaccines are known to protect in many other viral 
diseases, to date, the titer amount/level of neutralizing antibodies correlating with a 
decreased risk of SARS-CoV-2 infection nor a bone fide vaccine-induced functional 
correlate of protection has been determined/published. This trial will enable Cohort 13 
transplant subjects to receive their first immunization in this trial as soon as 3 months after 
their second injection in the parent trial. Based on the evaluation of ongoing safety and 
neutralizing antibody titer data after the 3rd vaccination (IMP injection 1 in this trial), using 
the methodology published by Khoury et al. 2021, a 4th vaccination (IMP injection 2) will be 
offered to this vulnerable population. The timeline will be 3 to 7 months after injection 1. 
Several breakthrough infections in transplant recipients have prompted a debate on how to 
provide additional protection to this vulnerable population (Tau et al. 2021; Qin et al. 
2021). Therefore, this data will help support an evidence-based rationale for the safety and 
efficacy of a 4th vaccination in these recipients and will provide details of consistency and 
adequacy of antibody responses. 
The safety and effectivity of Comirnaty has been demonstrated in more than 
25,000 subjects in clinical trials. The available pharmacovigilance data after Comirnaty 
administration to millions of individuals worldwide has confirmed its favorable safety profile 
with no specific safety concerns identified to date. The sponsor has accumulated a 
significant experience on the safety of Comirnaty in BNT162-02/C4591001 
(NCT04368728), which was the basis of the received Comirnaty authorization for 
emergency use or the conditional marketing authorization given in numerous countries. 
BNT162b2s01 and Comirnaty have the same LNP formulation and RNA components 
except that the RNAs slightly differ in their encoded open reading frame. The RNA 
component in BNT162b2s01 leads to expression of a Spike protein with the amino acid 
changes seen in the SARS-CoV-2 strain B.1.351, a widely recognized SARS-CoV-2 

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subjects or two boosting doses of Comirnaty in BNT162-04 trial subjects. There will be two 
groups. 
• 
Group A*: Trial subjects from BNT162-01 who received two injections of 30 µg 
Comirnaty will be randomized 2:1 to one booster injection 
(BNT162b2s01:Comirnaty). Day 1 (baseline in this trial) must occur ≥24 weeks 
after the last Comirnaty injection in the BNT162-01 trial. 
• 
Group B: Trial subjects in either the trial BNT162-01 or BNT162-04 who did not 
receive the full two vaccinations of 30 µg Comirnaty will be offered two injections of 
30 µg Comirnaty as per the conditional marketing authorization. Day 1 (baseline in 
this trial) must occur ≥12 weeks after receiving the last BNT162 candidate vaccine 
in the BNT162-01 or BNT162-04 trial. 
*Group A excludes transplant subjects from Cohort 13 of the BNT162-01 trial; consenting 
transplant subjects will enroll into Group B immunology subgroup and will receive one 
injection, which will be followed 3 to 7 months afterward by a second injection of 
Comirnaty. Henceforth this group is referred to as Group B transplants. 
All potential rollover volunteers must enroll in this trial within less than 18 months of their 
last injection of a BNT162 candidate vaccine in the parent BNT162-01 or BNT162-04 trials. 
BNT162-01 or BNT162-04 trial subjects, including trial subjects who are still in the follow-
up phase of their parent trial, will be actively informed about this rollover trial once it has 
received all necessary regulatory and ethical approvals. Depending on the timing of follow-
up in the parent trial, data from the parent trial may be used to determine eligibility in this 
rollover trial after the trial subject has consented. Once the trial subject has enrolled into 
this rollover trial, all safety reporting will occur through this rollover trial, this includes the 
reporting of AEs that are unresolved from the parent trial, SAEs, and clinical events of 
special interest (AESIs). 
A Safety Review Committee (SRC) will be reviewing emerging safety data at least every 
16 weeks until the last enrolled subject in Group A has completed 28 d of follow-up. The 
SRC may then decide to decrease the frequency of its cumulative safety data reviews to a 
minimum of once a year. The SRC will also review data from Group B (e.g., SUSARS) on 
an as needed basis but also specifically data emerging from the Group B transplant 
subjects. 
For a summary of the trial as a flow diagram, see the Schema in Section 1.2. For the 
planned assessments and visits, see the Schedule of Activities (SoA) in Section 1.3. 
Duration of all trial periods 
The planned trial duration for a subject in this trial is ~30 weeks (≤4 weeks of screening 
and ~26 weeks follow-up). 
The estimated planned trial start (first subject enrolled) and trial end (last subject last visit) 
are JUN 2021 and Q4 2022. 

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Trial population 
This trial will enroll subjects aged ≥18 years who received one or two previous injections of 
a BNT162 candidate vaccine in either the BNT162-01 trial or the BNT162-04 trial. 
Volunteers will not be enrolled if they have received any COVID-19 vaccine outside of the 
BNT162-01 trial or the BNT162-04 trial. 
The maximum number of trial subjects in the Group A (BNT162-01 trial subjects in 
Cohorts 1 to 14 who received 2 x Comirnaty 30 µg) will be 90 and in Group B (all other 
BNT162-01 or BNT162-04 trial subjects) will be 459. A subset of Group B (n = 129) will be 
asked to participate in an immunologic subset evaluation. 
Trial treatments 
IMP name: 
BNT162b2 (Comirnaty) or BNT162b2s01. 
Type: 
Vaccine (BNT162 RNA-LNP vaccine utilizing modRNA). 
Administration 
route: 
Intramuscular (IM); upper arm, musculus deltoideus. The same arm may be 
used for both immunizations. The non-dominant arm is preferred. 
Dosing regimen: 
Group A: One (at Day 1) IM injection with 30 µg of either Comirnaty or 
BNT162b2s01. 
Group B: Two (at Day 1 and Day 21) IM injections with 30 µg of Comirnaty, 
except Group B transplant subjects. 
Group B transplant subjects: Two IM injections of 30 µg of Comirnaty, with 
injection 2 administered 3 to 7 months after injection 1 (Day 1). 
The planned time points for injection of IMP for Groups A and B are 
provided in the SoA (Section 1.3). 
Sourcing: 
Provided centrally by the sponsor. 
Packaging and 
labeling: 
IMP will be provided in glass vials as open-label supply. Each vial will be 
labeled as required per country requirements. For details, see the Pharmacy 
Manual. 
 

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1.2 
Schema (graphical representation of the trial) 
 
Figure 1: 
Open-label rollover trial for BNT162-01 or BNT162-04 trial subjects 
* A subset of trial subjects will have in-depth immunological assessments, this will include the Group B transplant 
subjects (n = 15) who will receive their second injection based on SRC recommendation. 
“2” and “1” Randomization ratio. 
SRC = safety review committee. 

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i 
Only AEs related to IMP, AESIs, and SAEs. All AEs linked to confirmed COVID-19 cases will be recorded. For trial subjects who receive non-trial SARS-CoV-2 vaccinations, 
the AEs expected to be captured after these vaccinations are within the frame of post-marketing safety data reporting (see Section 8.3.1) and should not be recorded in the 
CRF. 
j 
Issue thermometer if not available from parent trial, for subjects to measure their body temperature each day and if they experience flu-like symptoms. 
k 
For subjects who receive non-trial SARS-CoV-2 vaccinations there will be no sampling in subsequent visits. Information about these vaccinations may be received outside of 
a planned visit and can be collected remotely, e.g., by phone. In such cases information on physical examination and vital signs can be skipped. However, AEs that occurred 
prior to administration of non-trial vaccine must be enquired and should be recorded as stated in footnote “i”. 
l 
Record any non-trial SARS-CoV-2 vaccinations that trial subjects receive during the trial in the CRF until the last trial visit. 
 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; CMI = cell mediated immunity; CRF = case report form; d = day; ELISA = enzyme-linked 
immunosorbent assay; EOT = end of trial; h = hour(s); IMP = investigational medicinal product; inj. = (IMP) injection; NAAT = nucleic acid amplification-based test; NATAB = 
neutralizing antibody titers and antibody binding; SAE = serious adverse event; SARS-CoV-2 = the virus leading to COVID-19; SoA = schedule of activities; WOCBP = women of 
childbearing potential. 
 

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j 
Only AEs related to IMP, AESIs, SAEs, and all AEs linked to confirmed COVID-19 cases will be recorded until the end of trial. For trial subjects who receive non-trial 
SARS-CoV-2 vaccinations, the AEs expected to be captured after these vaccinations are within the frame of post-marketing safety data reporting (see Section 8.3.1) and 
should not be recorded in the CRF. 
k 
Only for Group B transplant subjects: only AEs related to IMP, AESIs, SAEs, and all AEs linked to confirmed COVID-19 cases will be recorded until the end of trial. For trial 
subjects who receive non-trial SARS-CoV-2 vaccinations, the AEs expected to be captured after these vaccinations are within the frame of post-marketing safety data 
reporting (see Section 8.3.1) and should not be recorded in the CRF. 
l 
For subjects who receive non-trial SARS-CoV-2 vaccinations there will be no sampling in subsequent visits. Information about these vaccinations may be received outside of 
a planned visit and can be collected remotely, e.g., by phone. In such cases information on physical examination and vital signs can be skipped. However, AEs that occurred 
prior to administration of non-trial vaccine must be enquired and should be recorded as stated in footnotes “j” and “k”. 
m 
If applicable, Visit 7 or Visit 6 should be used to inform Group B transplant subjects (Cohort 13 of the BNT162-01 trial) on Dose 2 and informed consent must be collected. If 
Visit 6 is applicable, then Visit 7 must be skipped. Thereafter the SoA in Table 2a is applicable. 
n 
Record any non-trial SARS-CoV-2 vaccinations that trial subjects receive during the trial in the CRF until the last trial visit. 
o 
If a transplant subject consents to receive a second vaccination (i.e., 4th dose since the parent trial), the SoA in Table 2a is then applicable, there will be no blood sampling 
for CMI testing at the visit of consent (Visit 6 or Visit 7). 
p 
Only for Group B transplant subjects: record any non-trial SARS-CoV-2 vaccinations that trial subjects receive in the CRF. 
 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; CMI = cell mediated immunity; CRF = case report form; d = day; ELISA = enzyme-linked 
immunosorbent assay; EOT = end of trial; h = hour(s); IMP = investigational medicinal product; inj. = (IMP) injection; NAAT = nucleic acid amplification-based test; NATAB = 
neutralizing antibody titers and antibody binding; SAE = serious adverse event; SRC = safety review committee; SARS-CoV-2 = the virus leading to COVID-19; SoA = schedule of 
activities; WOCBP = women of childbearing potential. 
 
 

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Note: The SoA allows for ad hoc SARS-CoV-2 testing for symptomatic or asymptomatic subjects. 
a 
Brief (symptom-directed) physical examination; no height measurement. 
b 
Vital signs: systolic/diastolic blood pressure, pulse rate, respiratory rate, and body temperature; body weight only at Visit 0. 
c 
Vital signs pre-dose on days with IMP injection. 
d 
(Hematology) hemoglobin, hematocrit, red blood cell count, white blood cell count and differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet 
count. 
e 
Swabs will only be analyzed (sequenced) if serum nucleocapsid protein ELISA testing and/or NAAT-based SARS-CoV-2 testing detects SARS-CoV-2 (with or without 
symptoms). Oral swabs for SARS-CoV-2 sequencing must be collected at the same day/time (±30 minutes) as the oral swabs for NAAT-based SARS-CoV-2 for 
screening/surveillance. 
f 
Starting 28 d post injection 2, only AEs related to IMP, AESIs, SAEs, and all AEs linked to confirmed COVID-19 cases will be recorded until the end of trial. For trial subjects 
who receive non-trial SARS-CoV-2 vaccinations, the AEs expected to be captured after these vaccinations are within the frame of post-marketing safety data reporting (see 
Section 8.3.1) and should not be recorded in the CRF. 
g 
For subjects who receive non-trial SARS-CoV-2 vaccinations there will be no sampling in subsequent visits. Information about these vaccinations may be received outside of 
a planned visit and can be collected remotely, e.g., by phone. In such cases information on physical examination and vital signs can be skipped. However, AEs that occurred 
prior to administration of non-trial vaccine must be enquired and should be recorded as stated in footnote “f”. 
h 
Record any non-trial SARS-CoV-2 vaccinations that trial subjects receive during the trial in the CRF until the last trial visit. 
 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; CMI = cell mediated immunity; COVID-19 = corona virus disease 2019CRF = case report form; d = 
day; ELISA = enzyme-linked immunosorbent assay; EOT = end of trial; h = hour(s); IMP = investigational medicinal product; inj. = (IMP) injection; NAAT = nucleic acid 
amplification-based test; NATAB = neutralizing antibody titers and antibody binding; SAE = serious adverse event; SARS-CoV-2 = the virus leading to COVID-19; SoA = schedule 
of activities; WOCBP = women of childbearing potential. 
 

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neutralizing antibody titers and antibody binding; SAE = serious adverse event; SARS-CoV-2 = the virus leading to COVID-19; SoA = schedule of activities; WOCBP = women of 
childbearing potential. 

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TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY 
2 
1.1 
Trial synopsis 
2 
1.2 
Schema (graphical representation of the trial) 
8 
1.3 
Schedule of activities 
9 
TABLE OF CONTENTS 
20 
LIST OF TABLES 
23 
LIST OF FIGURES 
24 
ABBREVIATIONS/TERMS 
25 
2 
INTRODUCTION 
27 
2.1 
Background 
27 
2.1.1 
Overview of the disease 
27 
2.1.2 
Introduction to the trial treatment 
28 
2.2 
Trial rationale 
29 
2.3 
Benefit/risk assessment 
31 
2.3.1 
Risk assessment 
31 
2.3.2 
Benefit assessment 
34 
2.3.3 
Overall benefit/risk conclusion 
34 
3 
OBJECTIVES AND ENDPOINTS 
35 
4 
TRIAL DESIGN 
36 
4.1 
Overall design 
36 
4.2 
Scientific rationale for the trial design 
38 
4.3 
Justification for dose 
38 
4.4 
Trial completer and end of trial definitions 
38 
5 
TRIAL POPULATION 
39 
5.1 
Inclusion criteria 
39 
5.2 
Exclusion criteria 
40 
5.3 
Lifestyle considerations 
41 
5.4 
Screen failures 
41 
6 
TRIAL TREATMENTS 
41 
6.1 
IMPs administered 
42 
6.2 
Preparation/handling/storage/accountability 
42 
6.3 
Measures to minimize bias: randomization and blinding 
42 
6.4 
Trial treatment compliance 
43 
6.5 
Concomitant therapy 
43 

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6.6 
Dose modifications 
43 
6.7 
Access to trial treatment after the end of the trial 
43 
7 
DISCONTINUATION OF TRIAL TREATMENT AND TRIAL SUBJECT 
DISCONTINUATION/WITHDRAWAL 
44 
7.1 
Discontinuation of trial treatment 
44 
7.1.1 
Criteria to permanently discontinue IMP administration for Group B 
44 
7.1.2 
Criteria for temporarily delaying enrollment, randomization for Group A, or 
administration of IMP 
44 
7.2 
Trial subject discontinuation or withdrawal from the trial 
45 
7.3 
Lost to follow-up 
45 
7.4 
Replacement of permanently discontinued trial subjects 
46 
8 
TRIAL ASSESSMENTS AND PROCEDURES 
46 
8.1 
Efficacy assessments 
46 
8.2 
Safety assessments 
46 
8.2.1 
Physical examinations 
47 
8.2.2 
Vital signs including body weight 
47 
8.2.3 
Clinical laboratory tests 
47 
8.2.4 
Subject diaries 
48 
8.2.5 
Assessment of solicited local and systemic reactions 
48 
8.2.6 
Subject hotline 
48 
8.2.7 
Oral swabs for NAAT-based SARS-CoV-2 testing for screening and surveillance 
48 
8.2.8 
Serum for nucleocapsid protein testing 
49 
8.2.9 
Triggered SARS-CoV-2 genomic sequencing 
49 
8.3 
Adverse events and serious adverse events 
50 
8.3.1 
Time period and frequency for collecting AE, AESI, and SAE information 
50 
8.3.2 
Method of detecting AEs and SAEs 
50 
8.3.3 
Follow-up of AEs and SAEs 
50 
8.3.4 
Regulatory reporting requirements for SAEs 
51 
8.3.5 
Pregnancy 
51 
8.3.6 
Death events 
52 
8.3.7 
Disease-related events/outcomes not qualifying as AEs or SAEs 
52 
8.3.8 
Adverse events of special interest 
52 
8.4 
Treatment of overdose 
52 
8.5 
Treatments for specific adverse reactions 
53 
8.6 
Safety stopping criteria 
54 
8.7 
Pharmacokinetics 
54 
8.8 
Pharmacodynamics 
54 
8.9 
Genetics 
54 

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8.10 
Immune responses 
54 
8.10.1 
Neutralizing antibody titers and antibody binding (NATAB) 
55 
8.10.2 
Cell mediated immune responses 
55 
8.10.3 
Explorative biomarker/immunogenicity research 
55 
8.11 
Blood collection 
56 
9 
STATISTICAL CONSIDERATIONS 
56 
9.1 
Statistical hypotheses 
56 
9.2 
Sample size determination 
56 
9.3 
Analysis sets 
56 
9.4 
Statistical analyses 
57 
9.4.1 
General considerations 
57 
9.4.2 
Primary endpoints 
57 
9.4.3 
Secondary endpoints 
58 
9.4.4 
Exploratory endpoints 
59 
9.4.5 
Other safety analyses 
59 
9.4.6 
Other analyses 
60 
9.5 
Interim analyses 
60 
9.6 
Data monitoring committee 
60 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
60 
10.1 
Regulatory, ethical, and trial oversight considerations 
60 
10.1.1 
Regulatory and ethical considerations 
60 
10.1.2 
Financial disclosure 
61 
10.1.3 
Informed consent process 
61 
10.1.4 
Data protection 
61 
10.1.5 
Committees - SRC 
62 
10.1.6 
Dissemination of clinical trial data 
62 
10.1.7 
Data quality assurance 
62 
10.1.8 
Source documents 
63 
10.1.9 
Trial and site start and closure 
63 
10.1.10 
Publication policy 
64 
10.1.11 
Protocol preparation and approval 
64 
10.2 
Clinical laboratory tests 
64 
10.3 
Adverse events: Definitions and procedures for recording, evaluating, follow-up, and 
reporting 
65 
10.3.1 
Definition of AE and TEAE 
65 
10.3.2 
Assessments of intensity for solicited local and systemic reactions and laboratory 
abnormalities 
73 
10.4 
Contraceptive guidance and collection of pregnancy information 
76 
10.4.1 
Definitions 
76 

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10.4.2 
Contraception guidance 
77 
10.4.3 
Collection of pregnancy information 
77 
10.4.4 
Sperm donation 
78 
10.5 
Genetics 
78 
10.6 
Liver safety: Suggested actions and follow-up assessments 
78 
10.7 
Investigators and trial administrative structure 
78 
10.7.1 
Investigators and trial site personnel 
78 
10.7.2 
Trial site personnel assigned trial-related duties 
78 
10.7.3 
Contract research organizations 
79 
10.7.4 
The sponsor and sponsor’s personnel 
79 
10.8 
Country-specific requirements 
79 
10.9 
Protocol amendments and updates 
79 
10.9.1 
Protocol amendment 01 (update from protocol version 1.0 to 2.0) 
79 
10.9.2 
Protocol amendment 02 (update from protocol version 2.0 to 3.0) 
80 
10.9.3 
Protocol amendment 03 (update from protocol version 3.0 to 4.0) 
87 
10.10 
Data collection and management 
88 
10.10.1 
Case report forms 
88 
10.10.2 
Trial subject reported outcomes 
88 
10.10.3 
Data management 
88 
10.10.4 
Investigator’s Site File and the Trial Master File 
89 
10.11 
Other data 
89 
10.11.1 
Demographic data 
89 
10.11.2 
Medical history 
89 
11 
REFERENCES 
89 
 
LIST OF TABLES 
Table 1: 
Schedule of events for Group A (with one injection of either Comirnaty or 
BNT162b2s01) 
9 
Table 2: 
Schedule of events for Immunology Subgroup of Group B (with two injections of 
Comirnaty) h 
12 
Table 2a: Schedule of events for Immunology Subgroup of Group B transplant subjects 
(injection 2) 
15 
Table 3: 
Schedule of events for Group B (with two injections of Comirnaty) and no additional 
CMI or reactogenicity assessments 
17 
Table 4: 
Representative SARS-CoV-2 variants tracked by the WHO 
27 
Table 5: 
Local reaction grading scale 
73 
Table 6: 
Systemic reaction grading scale 
74 
Table 7: 
Laboratory abnormality grading scale 
75 
 

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LIST OF FIGURES 
Figure 1: 
Open-label rollover trial for BNT162-01 or BNT162-04 trial subjects 
8 

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Abbreviations: GISAID = Global Initiative on Sharing Avian Influenza Data; VOC = variant of concern; VOI = variant of interest; 
WHO = World Health Organization. 
Source: WHO webpage https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/, accessed 27 DEC 2021. 
2.1.2 
Introduction to the trial treatment 
The development of an RNA-based vaccine encoding a viral antigen that is translated to 
protein by the vaccinated organism to induce a protective immune response provides 
significant advantages over more conventional vaccine approaches. RNA-based vaccines 
have advantages over DNA, protein subunit, inactivated or live attenuated virus vaccines. 
First, safety: The RNA is degraded by normal cellular processes, is non-infectious, non-
integrating, and poses no risk of insertional mutagenesis. Second, efficiency: Delivery of 
RNA results in transient translation that can be controlled by modifications in the 
untranslated regions (UTRs), cap, poly(A) tail, and coding sequences. These modifications 
can make the RNA more stable and highly translatable. Efficient in vivo delivery can be 
achieved by formulating RNA into carrier LNPs that promote rapid uptake and enable RNA 
expression in the cytoplasm. Third, production: Manufacturing of conventional protein 
subunits, inactivated virus or replication-defective virus vaccines is time consuming and 
involves multiple pieces of manufacturing equipment. Protein vaccine production and 
purification require optimization for each mammalian or insect cell culture system. In 
addition, each production system introduces the potential for improper folding and altered 
glycosylation patterns of the protein, particularly when produced in insect cells. In contrast, 
RNA-based vaccine production does not require individualized cell culture systems and 
unique purification systems for each vaccine antigen. Uniformly optimized transcription 
and purification techniques can be used to produce any RNA sequence. Furthermore, 
because RNA sequences are processed in vivo as would occur during viral infection, 
glycosylation patterns of the antigens are similar to those seen after natural infection. 
As demonstrated by the SARS-CoV-2 RNA-LNP-based vaccine Comirnaty, LNP-
formulated RNA-based vaccines provide one of the most flexible, scalable and fastest 
approaches to provide protection against the emerging viruses like SARS-CoV-2 (Mulligan 
et al. 2020; Rauch et al. 2018; Sahin et al. 2014; Walsh et al. 2020). The safety and 
effectivity of Comirnaty has been demonstrated in more than 25,000 subjects in clinical 
trials. The available pharmacovigilance data after Comirnaty administration to millions of 
individuals worldwide has confirmed its favorable safety profile with no specific safety 
concerns identified to date. 
BNT162b2s01 and Comirnaty have the same LNP formulation and RNA components 
except that the RNAs differ slightly in their encoded open reading frame. The RNA 
component in BNT162b2s01 leads to expression of a Spike protein with the amino acid 
changes seen in the SARS-CoV-2 strain B.1.351, a widely recognized SARS-CoV-2 
variant originally identified in the Republic of South Africa (Table 4). 
Please see Section 2.3 for a detailed benefit/risk analysis. For further details on the 
BNT162 family of RNA-based vaccines, see the current BNT162 investigator’s brochure 
(IB). 

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2.2 
Trial rationale 
BioNTech has developed RNA-based vaccine candidates using a platform approach that 
enables the rapid development of vaccines against emerging viral diseases, including 
SARS-CoV-2. The BNT162b platform uses modRNA. The BNT162b platform member 
BNT162b2 (Comirnaty) has received emergency use authorization or conditional 
marketing authorization in numerous countries worldwide for the prevention of COVID-19 
disease. As demonstrated by Comirnaty, LNP-formulated RNA-based vaccines provide 
one of the most flexible, scalable and fastest approaches to provide protection against the 
emerging viruses like SARS-CoV-2 (Mulligan et al. 2020; Rauch et al. 2018; Sahin et al. 
2014; Walsh et al. 2020). 
This rollover trial (BNT162-14) will enroll BNT162-01 or BNT162-04 trial subjects; the 
BNT162-01 or BNT162-04 trials are also referred to as parent trials. The trial subjects 
represent a unique group of BNT162 vaccinees because their antibody and T-cell 
responses to SARS-CoV-2 antigens have been longitudinally characterized in the parent 
trials. Longitudinal characterization of the continuum of antibody and T-cell responses to 
BNT162 vaccines given to outbred human populations where pressure on the virus from 
genetics and evolving immune responses is simultaneously occurring, provides an 
opportunity for new and prescient insights into how the virus may evolutionarily adapt. 
Studies have demonstrated that Comirnaty protects against severe COVID-19 disease 
caused by the first generation of SARS-CoV-2 viral strains (called “L strain”, reference, or 
“wild type”) at least 6 months (unpublished data). The trial provides the opportunity to 
assess vaccine and booster induced durability of immune responses in context of more 
recent data on natural infection and cross-neutralization immunity. For example, SARS-
CoV-2 infection and RNA vaccines such as Comirnaty induce cross-neutralization to 
multiple, more recently identified viral variants, some of which are identified as variants of 
concern (VOC) (Liu et al. 2021; Widge et al. 2021). In addition, more recent data suggests 
that natural infection will induce sustained B and T cell memory responses for at least six 
months (Dan et al. 2021; Zuo et al. 2021). 
Thus, the BNT162-14 trial proposes to evaluate the added value of booster injections of 
Comirnaty or a closely related BNT162 vaccine (BNT162b2s01 [also referred to as 
BNT162b2 (B.1.351)]), which targets the VOC strain B.1.351 originally identified in the 
Republic of South Africa. In addition, durability of immune responses will also be assessed 
in a second group of subjects within Group B who received an alternative BNT162 vaccine 
in the BNT162-01 or BNT162-04 trial and who will be offered two injections of 30 µg 
Comirnaty as per the conditional marketing authorization as long as they have not 
received any COVID-19 vaccine independent of the parent trials. The selected subjects for 
in-depth immunologic assessments in Group B may provide additional insights (e.g., 
immuno-dominance, increasing breadth of responses to select antigens) because they 
were primed with differing antigen constructs (i.e., vaccine candidates other than 
Comirnaty) or differing doses of Comirnaty, where protection against COVID-19 disease 
was not evaluated and dosing may have been suboptimal. 
BNT162-14 will also descriptively assess if a third vaccination may improve SARS-CoV-2 
spike neutralizing antibodies in the BNT162-01 Cohort 13 transplant subjects. Based on 
published data collected from vaccinating transplant recipients with Comirnaty and data 

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from the BNT162-01 trial, transplant subjects demonstrate poor neutralizing antibody 
responses to SARS-CoV-2 Spike epitopes (Boyarsky et al. 2021; Sattler et al. 2021; 
Rincon-Arevalo et al. 2021), not unexpectedly, given the known poor antibody responses 
induced by influenza vaccines in solid organ transplant patients. Safety data from 
Cohort 13 subjects in the parent trial and a 3rd and 4th vaccination of Comirnaty in healthy 
volunteers supports evaluation of three or four vaccinations in the Cohort 13 transplant 
subjects (per communication of Data Monitoring Committee reviewing trial 
BNT162-02/CA4591001 [NCT04368728] Amendment 14). While high levels of neutralizing 
antibodies elicited by viral vaccines are known to protect in many other viral diseases, to 
date, the titer amount/level of neutralizing antibodies correlating with a decreased risk of 
SARS-CoV-2 infection nor a bone fide vaccine-induced functional correlate of protection 
has been determined/published. This trial will enable Cohort 13 transplant subjects to 
receive their first immunization in this trial as soon as three months after their second 
injection in the parent trial.  
While monitoring transplant subject safety and reviewing immunogenicity data at 50 days 
after the third vaccination, an SRC decision was made to further evaluate the possibility of 
enhancing antibody response and monitoring the sustainability of antibody titers. The 
interim analysis post 50 days, using an evidence-based model (Khoury et al. 2021), 
demonstrated safety and protective efficacy (4-fold of convalescent) in up to 70% of the 
recipients. However, the response was inconsistent and heterogenous. There was also a 
limitation due to lack of CD4 counts or hypogammaglobulinemia information in low, 
negative, and/or inconsistent responders. Recently published evidence (Alejo et al. 2021) 
demonstrated that the fourth dose of vaccine in transplant recipients boosted immunologic 
response in low responders as well as non-responders. Another recently published data 
also from Kamar et al. 2021 suggested significant improvement of antibody titers 4 weeks 
after Dose 4 in solid organ transplant recipients who received the fourth dose 65 days after 
the third dose. Therefore, safety and efficacy data post-injection 2 in this trial will help 
support evidence-based rationale for the safety and efficacy of a 4th vaccination in this 
vulnerable population. 
The safety and effectivity of Comirnaty has been demonstrated in more than 
25,000 subjects in clinical trials. The available pharmacovigilance data after Comirnaty 
administration to millions of individuals worldwide has confirmed its favorable safety profile 
with no specific safety concerns identified to date. The sponsor has accumulated a 
significant experience on the safety of Comirnaty in BNT162-02/C4591001 
(NCT04368728), which was the basis of the received Comirnaty authorization for 
emergency use or the conditional marketing authorization given in numerous countries. 
BNT162b2s01 and Comirnaty have the same LNP formulation and RNA components 
except that the RNAs slightly differ in their encoded open reading frame. The RNA 
component in BNT162b2s01 leads to expression of a Spike protein with the amino acid 
changes seen in the SARS-CoV-2 strain B.1.351, a widely recognized SARS-CoV-2 
variant originally identified in the Republic of South Africa. Based on the emerging 
reactogenicity and safety data from vaccine boosting of Phase III trial subjects in 
BNT162-02/C4591001 (NCT04368728), Amendment 14, with BNT162b2 or 
BNT162b2s01, no new safety concerns are anticipated with a 3rd or 4th vaccinations in this 
trial. Serious adverse events (SAEs) will be recorded throughout the trial and they will be 

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reported in an expedited fashion if they meet Suspected Unexpected Serious Adverse 
Reactions (SUSAR) criteria. However, to further support development of multiple 
sequential vaccinations with this RNA-LNP platform, reactogenicity data will still be 
collected from subjects who are randomized to Comirnaty or BNT162b2s01 (Group A) and 
a selected subset of subjects who receive the conditionally authorized Comirnaty regimen 
(Group B). 
2.3 
Benefit/risk assessment 
Typically, healthy trial volunteers participating in clinical trials can expect no direct health 
benefits; however, subjects in this trial are offered a conditionally authorized SARS-CoV-2 
vaccine or boosters of the same or similar vaccine, which may or may not provide benefit 
in continuing to protect against COVID-19 disease (see Benefit assessment Section 2.3.2). 
This trial is also designed to minimize the risks to trial subjects while maximizing the 
potential value of knowledge it is designed to provide. 
For further information on the expected benefits and risks for injection with Comirnaty, 
including the reference safety information, see the current BNT162 IB. 
2.3.1 
Risk assessment 
General risks of vaccines: 
• 
The vaccines used in this trial may have side effects, some of which are listed 
below. Please note that these lists do not include all individual side effects ever 
seen with these vaccines. The more serious or common side effects with a known 
or possible relationship to the vaccine are listed. 
• 
Rarely, a vaccine may cause an allergic reaction such as rash or difficulty 
breathing. Allergic reactions may be life-threatening. All trial subjects will be 
queried for a history of reactions to vaccines and this vaccine’s excipients. 
• 
Side effects seen from giving a vaccine by injection into the muscle include local 
reactions at the injection site such as redness, itchiness, tenderness, pain, and 
swelling. 
• 
All vaccines can cause fever, chills, rash, aches and pains in the muscles or joints, 
nausea and loss of appetite, headache, dizziness, and feeling tired. Most people 
are still able to do their planned activities after getting a vaccine. Rarely, people 
experience side effects that limit their normal activities or make them go to their 
doctor. 
• 
Very rarely, a vaccine may cause an autoimmune disease in a person or may 
make an autoimmune disease worse. 
• 
For other known risks related to Comirnaty and anticipated risks related to 
BNT162b2s01, refer to the current BNT162 IB. 

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o BNT162b2 has received temporary authorization for emergency supply in 
46 countries and licenses or conditional marketing authorizations in 
46 countries globally under the tradename Comirnaty. Full approval of a 2-
dose regimen of BNT162b2 30 μg in individuals ≥16 years of age was 
granted by the US Food and Drug Administration (FDA) on 23 AUG 2021. 
The safety profile of BNT162b2 based on available data in the ongoing 
Phase II/III trial BNT162-02 / C4591001 is favorable. Since its first marketing 
authorization in December 2020, BNT162b2 has been administered to 
hundreds of millions of individuals worldwide. 
o The safety of BNT162b2 after two doses was evaluated in subjects 5 years 
of age and older. The trial BNT162-02 / C4591001 enrolled ~46,000 subjects 
12 years of age or older. The trial BNT162-07 / C4591007 (NCT048166443) 
enrolled ~2,300 subjects 5 through less than 12 years of age. Additionally, 
306 existing Phase III subjects at least 18 through 55 years of age received a 
booster dose (third dose) of BNT162b2 ~6 months after the second dose. 
The overall safety profile for the booster dose (third dose) was similar to that 
seen after two doses. 
o The safety of BNT162b2 was evaluated in subjects 16 years of age and older 
after 2 doses. In the trial BNT162-02 / C4591001, a total of 22,026 subjects 
16 years of age or older received at least one dose of BNT162b2 and a total 
of 22,021 subjects 16 years of age or older received placebo (as of the data 
cutoff date of 13 MAR 2021). The most frequent adverse reactions in 
subjects 16 years of age and older that received two doses were injection 
site pain (>80%), fatigue (>60%), headache (>50%), myalgia (>40%), chills 
(>30%), arthralgia (>20%), pyrexia and injection site swelling (>10%) and 
were usually mild or moderate in intensity and resolved within a few days 
after vaccination. A lower frequency of reactogenicity events was associated 
with greater age. The safety profile in 545 subjects receiving BNT162b2, that 
were seropositive for SARS-CoV-2 at baseline, was similar to that seen in 
the general population. The trial BNT162-02 / C4591001 also included 
200 subjects with confirmed stable human immunodeficiency virus (HIV) 
infection. The safety profile of the subjects receiving BNT162b2 (n = 100) in 
the individuals with stable HIV infection was similar to that seen in the 
general population. 
o The safety of BNT162b2 was evaluated in subjects 18 years of age and older 
after booster dose (third dose). A subset from trial BNT162-02 / C4591001 
Phase II/III subjects of 306 adults at least 18 through 55 years of age who 
completed the primary BNT162b2 2-dose course, received a booster dose 
(third dose) of BNT162b2 ~6 months (range of 4.8 to 8.0 months) after 
receiving Dose 2. The most frequent adverse reactions in subjects 18 
through 55 years of age were injection site pain (>80%), fatigue (>60%), 
headache (>40%), myalgia (>30%), chills and arthralgia (>20%). 

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o The most common adverse reactions (seen ≥1/10) were headache, diarrhea, 
arthralgia, myalgia, injection site pain, fatigue, chills, pyrexia, and injection 
site swelling, and (seen ≥1/10 to <1/10) were vomiting, nausea, and injection 
site redness. 
o Special warnings and precautions for use have been defined for anaphylaxis, 
myocarditis and pericarditis, acute severe febrile illness, coagulation 
disorders, for immunocompromised individuals, and for stress-related 
responses associated with the process of vaccination itself. For details see 
the current BNT162 IB. 
o Hypersensitivity to the BNT162b2 active substance and/or to any of the 
excipients is a contraindication.  
o Although not seen to date, it cannot yet be ruled out that the trial IMPs could 
make a later COVID-19 illness more severe. 
Risks associated with trial-specific procedures: 
• 
There is the risk of bleeding, bruising, hematoma formation, and infection at the 
venipuncture site. To minimize this risk, only appropriately qualified personnel will 
draw blood. 
• 
The volume of blood drawn at any visit is kept to the amounts required to support 
the objectives of this trial, and the total blood volume drawn over any 28 d period 
will remain less than that drawn when donating blood (i.e., less than 450 mL, a 
typical blood donation volume). 
Mitigations for vaccine-related and trial risks: 
• 
In general, the listed risks of IM injection can be managed using routine symptom-
driven standard of care. Treatment of these events is dependent on the discretion 
of the investigators. As Comirnaty has received conditional marketing authorization 
and been provided to millions of people without new or significant safety signals, 
procedures routine for monitoring Phase I trials are not planned. 
• 
All trial-specific procedures will be performed by qualified trial site personnel. 
• 
Trial subjects will be observed at the site for ~1 h after each IMP injection. 
• 
Equipment to treat anaphylaxis will be readily available. 
• 
To minimize the risk to trial subjects, the Medical Monitor and the SRC will 
regularly review and evaluate the safety data including any emerging SAEs or 
AESIs. For details, see Section 10.1.5. 
• 
Human reproductive safety data are limited for Comirnaty. Therefore, although 
human teratogenicity is not suspected based on the intended pharmacology of the 
compound, the use of one highly effective method of contraception is required in 
this trial (see Section 10.4). For further details, see in the current BNT162 IB. 

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The risks and mitigations linked to the COVID-19 pandemic while participating in the trial 
include the following: 
• 
The risk of becoming SARS-CoV-2 infected or unknowingly spreading the virus 
during participation in the trial; therefore, trial subjects will continue to be required 
to practice social distancing and infection prevention practices. 
• 
Use of a Subject hotline for subjects to contact the trial site during their 
participation should they require guidance or experience symptoms suggestive of 
SARS-CoV-2 infection. If the subject reports symptoms of illness, e.g., enhanced 
respiratory disease or flu-like symptoms, the subject will be asked to return to the 
site for diagnostic measures. More specifically, respiratory disease or progression 
of flu-like symptomatology, such as non-resolution of the symptoms after 3 d, i.e., 
symptom kinetics that are inconsistent with SARS-CoV-2 RNA immunization, will 
trigger diagnostic measures, i.e., antigen and diagnostic nucleic acid SARS-CoV-2 
testing with reflexive viral sequencing. 
2.3.2 
Benefit assessment 
The vaccine Comirnaty has been given conditional marketing authorization in numerous 
countries worldwide for the prevention of COVID-19 disease. Thus, if subjects entering this 
trial did not receive injections of Comirnaty in their previous trial, they will be offered two 
injections of Comirnaty in this trial, and thus should have protection against severe 
COVID-19 disease. 
If two injections of 30 µg Comirnaty were received in the parent trial, a booster injection 
with Comirnaty or BNT162b2s01 (a similar vaccine targeting a different SARS-CoV-2 
strain) will be given in this trial. A booster injection could potentially enhance the durability 
of protection against COVID-19 disease or hypothetically help with protection from COVID-
19 disease resulting from other circulating viral strains. 
Participation in this trial could also help the trial subject indirectly. Clinical laboratory tests, 
physical exams and other safety assessments received while participating in this trial could 
uncover previously undiagnosed health problems. The trial subject will have access to 
real-time SARS-CoV-2 diagnostic testing. Also, by participating in this trial, trial subjects 
may better understand of how vaccines can help protect against COVID-19 disease. 
2.3.3 
Overall benefit/risk conclusion 
Overall, the sponsor considers the benefit/risk ratio to be acceptable. 

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• 
Group B: Trial subjects in either the trial BNT162-01 or BNT162-04 who did not 
receive the full two vaccinations of 30 µg Comirnaty will be offered two injections of 
30 µg Comirnaty as per the conditional marketing authorization. Day 1 (baseline in 
this trial) must occur ≥12 weeks after receiving the last BNT162 candidate vaccine 
in the BNT162-01 or BNT162-04 trial. 
*Group A excludes transplant subjects from Cohort 13 of the BNT162-01 trial; consenting 
transplant subjects will enroll into Group B immunology subgroup and will receive one 
injection, which will be followed 3 to 7 months afterward by a second injection of 
Comirnaty. Henceforth this group is referred to as Group B transplants. 
All potential rollover volunteers must enroll in this trial within less than 18 months of their 
last injection of a BNT162 candidate vaccine in the parent BNT162-01 or BNT162-04 trials. 
BNT162-01 or BNT162-04 trial subjects, including trial subjects who are still in the follow-
up phase of their parent trial, will be actively informed about this rollover trial once it has 
received all necessary regulatory and ethical approvals. Depending on the timing of follow-
up in the parent trial, data from the parent trial may be used to determine eligibility in this 
rollover trial after the trial subject has consented. Once the trial subject has enrolled into 
this rollover trial, all safety reporting will occur through this rollover trial, this includes the 
reporting of AEs that are unresolved from the parent trial, SAEs, and clinical events of 
special interest (AESIs). 
A Safety Review Committee (SRC) will be reviewing emerging safety data at least every 
16 weeks until the last enrolled subject in Group A has completed 28 d of follow-up. The 
SRC may then decide to decrease the frequency of its cumulative safety data reviews to a 
minimum of once a year. The SRC will also review data from Group B (e.g., SUSARS) on 
an as needed basis but also specifically data emerging from the Group B transplant 
subjects. 
For a summary of the trial as a flow diagram, see the Schema in Section 1.2. For the 
planned assessments and visits, see the Schedule of Activities (SoA) in Section 1.3. 
This trial will enroll healthy volunteers aged ≥18 years who received one or two previous 
injections of a BNT162 candidate vaccine in either the BNT162-01 trial or the BNT162-04 
trial. Volunteers will not be enrolled if they have received any COVID-19 vaccine outside of 
their parent trial. 
The maximum number of trial subjects in the Group A (BNT162-01 trial subjects in 
Cohorts 1 to 14 who received 2 x Comirnaty 30 µg) will be 90 and in Group B (all other 
BNT162-01 or BNT162-04 trial subjects) will be 459. A subset of Group B (n = 129) will be 
asked to participate in an immunologic subset evaluation. 
Group A (previous 2 x Comirnaty 30 µg recipients from BNT162-01): n = 90 
• 
BNT162-01 trial Cohorts 2 and 10: n = 24 
• 
BNT162-01 trial Cohort 12: n = 31 (of 90) 
• 
BNT162-01 trial Cohort 13: n = 15 HIV-infected subjects 
• 
BNT162-01 trial Cohort 14: n = 20 

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The immunology subset of Group B (BNT162-01 or BNT162-04 trial subjects who did not 
receive 2 x Comirnaty 30 µg and Cohort 13 transplant patients) whom will be asked to 
participate in reactogenicity and detailed immunologic assessments: n = 129 
• 
BNT162-01 trial - BNT162b1 Cohorts 2, 5 and 1: n = 36 (of 120) 
• 
BNT162-01 trial - BNT 162b2 Cohort 11: n = 30 
• 
BNT162-01 trial - BNT 162b2 Cohort 13: n = 15 transplant subjects 
• 
BNT162-04 trial - BNT162b3 younger Cohorts 1, 2, 5, 7: n = 48 (of 96) 
4.2 
Scientific rationale for the trial design 
The scientific rationale for this open-label trial is the following: 
• 
to describe changes in vaccine-induced durability and T cell, B cell and antibody 
breadth to SARS-CoV-2 antigens before and after booster vaccines; 
o to assess if booster vaccines improve immune responses against variant 
B.1.351; 
o to describe changes in vaccine-induced correlates of protection (if identified 
from other BNT162 vaccine studies); 
• 
to assess safety of additional BNT162 booster vaccines; 
• 
to describe sequences of SARS-CoV-2 infections to increase understanding of the 
current SARS-CoV-2 strains in circulation and document if potential signs of 
immune pressure from vaccines, genetics, etc. on the virus are observed; and 
• 
to assess changes in immune responses in transplant subjects with 3rd and 4th 
vaccinations. 
4.3 
Justification for dose 
Trial subjects from the BNT162-01 and BNT162-04 trials who did not receive two injections 
with 30 µg Comirnaty will be offered the Comirnaty dose and injection schedule that 
received conditional marketing authorization. This is the same dose evaluated in the 
Phase III trial (BNT162-02/C4591001) and the dose for which the available 
pharmacovigilance data after Comirnaty administration to millions of individuals worldwide 
has confirmed a favorable safety profile with no specific safety concerns. 
Trial subjects from the BNT162-01 trial who did receive two injections of 30 µg Comirnaty 
will be offered a single 30 µg Comirnaty or BNT162b2s01 booster injection. The safety and 
immunogenicity of the candidate vaccine BNT162b2s01 is not anticipated to be any 
different than for the prototype vaccine Comirnaty. 
4.4 
Trial completer and end of trial definitions 
A trial subject is considered to have completed the trial if they have completed all planned 
visits as listed in the SoA (see Section 1.3). 
The end of the trial is defined as the date of the last visit of the last subject in the trial. 

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5 
TRIAL POPULATION 
Investigators should always use good clinical judgment in considering a volunteer’s overall 
fitness for trial participation. Some volunteers may not be appropriate for enrollment in the 
rollover trial even if they meet all inclusion/exclusion criteria. 
5.1 
Inclusion criteria 
Volunteers are eligible for enrollment into this trial if all of the following criteria apply: 
1. Have given informed consent by signing the informed consent form (ICF) before 
initiation of any trial-specific procedures. 
2. Willing and able to comply with scheduled visits, treatment schedule, laboratory tests, 
lifestyle restrictions (including those requested by the German and federal 
Governments, e.g., to follow good practices to reduce chances of spreading 
COVID-19), and other requirements of the trial. 
3. Have received BNT162 vaccine candidates in the BNT162-01 or BNT162-04 trials. 
4. Remain overall healthy (i.e., has not medically deteriorated significantly since 
participation in the parent trial, is not anticipated to die in the next 26 weeks, and is 
able to provide blood as specified by the trial without anticipated, deleterious medical 
consequences) in the clinical judgment of the investigator based on medical history and 
physical examination. Screening clinical laboratory tests are to assess the subjects 
“new baseline” unless required for eligibility (e.g., platelets). 
Note: In particular, caution should be used with a subject who has a history of 
cardiovascular disease, e.g., myocarditis, pericarditis, myocardial infarction, congestive 
heart failure, cardiomyopathy or clinically significant arrhythmia. 
5. Agree not to enroll in another trial of an IMP, starting after Visit 0 and continuously until 
Visit 5 (Day 50). 
6. Less than 18 months have passed since their last IMP injection in their parent trial. 
7. If they received 30 µg Comirnaty twice in the BNT162-01 trial, Visit 1 in this trial is 
≥24 weeks after their last IMP injection, unless the subject is a Cohort 13 transplant 
subject of the BNT162-01 trial. 
8. If they received any other BNT162 vaccine candidate than Comirnaty in the BNT162-01 
or BNT162-04 trial or are a Cohort 13 transplant subject, Visit 1 in this trial is 
≥12 weeks after their last IMP injection. 
9. Have not been diagnosed with SARS-CoV-2 infection in the 12 weeks prior to Day 1 
(baseline). Subjects who screen-fail on this criterion may be rescreened. 
Laboratory inclusion values 
Hemogram/complete blood count (CBC): 
10. Platelets = 125,000 to 550,000/mm3. 

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Chemistry: 
11. Chemistry panel: the following apply: alkaline phosphatase (ALP), alanine 
aminotransferase (ALT), and aspartate aminotransferase (AST) are <3.0 times the 
upper limit of normal, and glomerular filtration rate (GFR) is ≥ 40 mL/min/1.73 m2. 
Note: Other collected chemistries per the SoA are considered “baseline” values 
should serious adverse events occur in this trial. 
Immunocompromised subjects/BNT162-01 Cohort 13: 
12. Immunocompromised subjects may be included if their clinical laboratory values are 
stable in the context of their disease, and if there is no acute deterioration present with 
the expected need to change their therapy within the 2 weeks after the anticipated trial 
vaccination. 
Reproductive status 
13. Women of childbearing potential (WOCBP) must test negative in a urine beta-human 
chorionic gonadotropin (β-HCG) test at Visits 0 and 1. Women that are post-
menopausal or permanently sterilized will be considered as not having reproductive 
potential. 
14. WOCBP must agree to practice a highly effective form of contraception during the trial, 
starting at screening and continuously until Visit 5 (Day 50). For guidance on what is 
considered a “highly effective form of contraception”, see Section 10.4.2. 
15. WOCBP must confirm that they practiced one highly effective form of contraception for 
the 14 d prior to screening. 
16. WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the trial, starting after Visit 0 and continuously until Visit 5 (Day 50). 
17. Men who are sexually active with a WOCBP and have not had a vasectomy must 
agree to use a highly effective form of contraception with their female partner of 
childbearing potential during the trial, starting after Visit 0 and continuously until Visit 5 
(Day 50). 
18. Men must be willing to refrain from sperm donation, starting after Visit 0 and 
continuously until Visit 5 (Day 50). 
5.2 
Exclusion criteria 
Volunteers are not eligible for enrollment if any of the following criteria apply: 
1. Have received any SARS-CoV-2 vaccine outside of the BNT162-01 or BNT162-04 
trials. 
2. Have a known allergy, hypersensitivity, or intolerance to the planned IMP including any 
excipients of the IMP. 
3. Have a current febrile illness (body temperature ≥38.0°C) or other acute illness within 
48 h prior to Day 1/IMP injection in this trial. Subjects who screen-fail on this criterion 
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4. Have received a live or live attenuated vaccine within 30 d prior to Day 1/IMP injection, 
or any other vaccination within 14 d prior to Day 1/IMP injection. Subjects who screen-
fail on this criterion may be rescreened. 
5. Have an ongoing AE assessed as related to any BNT162-01 or BNT162-04 trial 
vaccine. 
5.3 
Lifestyle considerations 
Strenuous physical activity will not be allowed on visit days. When at the trial site, trial 
subjects will not be allowed to smoke or to drink alcohol. 
The trial subjects will be required to remain at the site for ~1 h after each IMP injection. 
Subjects will be asked to avoid strenuous exercise beyond their usual exercise routine for 
7 d after each IMP administration. 
Trial subjects will be updated on the most recent local guidance on recommended social 
behaviors for people who have been vaccinated, e.g., continued social distancing because 
of an increasing number of more infectious variants and following good practices to reduce 
their chances of being infected or asymptomatically spreading COVID-19. 
5.4 
Screen failures 
Screen failures are defined as individuals who consent to participate in the trial but who 
are not subsequently allocated to IMP. 
For subjects who may not have passed all of the screening requirements such as one of 
the following:  
• 
diagnosis of SARS-CoV-2 infection within 12 weeks prior to Day 1, 
• 
febrile illness within 48 hours prior to Day 1, or  
• 
required (clinically indicated) vaccine within its exclusion time period (i.e., 2 or 4 
weeks) prior to Day 1 
medical judgement may be used to decide if and when to rescreen as long as the subject 
is <18 months from their last IMP injection of the parent trial prior to Day 1. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screening failures to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, date the ICF was signed, the reasons for screen 
failures, and any SAEs, if applicable. 
6 
TRIAL TREATMENTS 
Trial treatment is defined as any investigational treatment(s), marketed product(s), 
intended to be administered to a trial subject according to the trial protocol. 

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6.1 
IMPs administered 
IMP name: 
BNT162b2 (Comirnaty) or BNT162b2s01. 
Type: 
Vaccine (BNT162 RNA-LNP vaccine utilizing modRNA). 
Administration 
route: 
Intramuscular (IM); upper arm, musculus deltoideus. The same arm may be 
used for both immunizations. The non-dominant arm is preferred. 
Dosing regimen: 
Group A: One (at Day 1) IM injection with 30 µg of either Comirnaty or 
BNT162b2s01. 
Group B: Two (at Day 1 and Day 21) IM injections with 30 µg of Comirnaty, 
except Group B transplant subjects. 
Group B transplant subjects: Two IM injections of 30 µg of Comirnaty, with 
injection 2 administered 3 to 7 months after injection 1 (Day 1). 
The planned time points for injection of IMP for Groups A and B are 
provided in the SoA (Section 1.3). 
Sourcing: 
Provided centrally by the sponsor. 
Packaging and 
labeling: 
IMP will be provided in glass vials as open-label supply. Each vial will be 
labeled as required per country requirements. For details, see the Pharmacy 
Manual. 
 
6.2 
Preparation/handling/storage/accountability 
The principal investigator is responsible for IMP (and any components thereof) 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and final 
disposition records). 
For instructions on IMP preparation, handling, and storage, see the Pharmacy Manual. 
All IMP (and any components thereof) must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized trial site 
personnel. 
The preparation of solution for injection will be performed by aseptic handling procedures 
by pharmaceutical personnel or other trained personnel at the trial site. Further guidance 
and information for the final disposition of unused IMP (and any components thereof) is 
provided in the Pharmacy Manual. 
6.3 
Measures to minimize bias: randomization and blinding 
This is an open-label trial but: 
• 
Group A trial subjects will be randomized 2:1 to BNT162b2s01:Comirnaty using an 
online randomization tool. 
• 
Group B trial subjects will be allocated to trial treatment without active 
randomization and selected subjects will be asked to participate in the detailed 
immunogenicity assessment based on their parent trial cohort. 

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6.4 
Trial treatment compliance 
All IMP injections will be administered by a trial site physician. 
The date and time of each IMP injection must be recorded in the source documents and 
recorded in the case report form (CRF). The IMP dose and trial subject identification will 
be confirmed at the time of administration by a member of the trial site personnel other 
than the person administering the IMP. 
6.5 
Concomitant therapy 
Trial subjects should not receive any live or live attenuated vaccination within 30 d before 
or after any trial injection e.g., measles, mumps, and rubella (MMR); oral polio vaccine 
(OPV); varicella; yellow fever unless medically indicated e.g., rabies. 
Trial subjects should not receive any other vaccines within 14 d before or after any trial 
injection, e.g., influenza, tetanus, pneumococcal, hepatitis A or B. When possible standard 
or care vaccinations should be planned with the trial injections in mind. 
Recording of concomitant therapy for Group A: any medication or vaccine (including over-
the-counter or prescription medicines, vitamins, and/or herbal supplements, or other 
specific categories of interest), that the trial subject receives starting after Visit 0 until 
Visit 5, and any medications due to medical history started before Visit 0 must be recorded 
in the CRF along with the: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
Concomitant therapy recording is not required for Group B but will be recorded on the SAE 
or AESI report. 
Any non-trial SARS-CoV-2 vaccine, that trial subjects receive starting after Visit 0 until the 
last trial visit (at the times listed in the SoA, Section 1.3) must be recorded in the CRF. 
6.6 
Dose modifications 
Not applicable to this trial. 
6.7 
Access to trial treatment after the end of the trial 
Not applicable. 

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7 
DISCONTINUATION OF TRIAL TREATMENT AND TRIAL 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of trial treatment 
7.1.1 
Criteria to permanently discontinue IMP administration for 
Group B 
Note that discontinuation from IMP does not represent withdrawal/discontinuation from the 
trial. Trial subjects permanently discontinued from IMP administration should still complete 
all assessments planned in the SoA (Section 1.3). 
Reasons for definitive discontinuation from IMP include the following: 
• 
SAEs warranting discontinuation; 
• 
other trial-related safety concerns; 
• 
subject or investigator request; 
• 
pregnancy; 
• 
deterioration in trial subject health at the time of IMP injection (at the discretion of 
the investigator). 
In the event of trial subject permanent discontinuation from IMP, it must be documented on 
the appropriate CRF/in the medical records if the trial subject is discontinuing further 
receipt of trial treatment, or also from trial procedures, post-treatment follow-up, future 
collection of additional information and/or consent. 
7.1.2 
Criteria for temporarily delaying enrollment, randomization for 
Group A, or administration of IMP 
The are no criteria defined which trigger temporarily delaying trial subject enrollment or 
randomization. 
There are medical conditions or situations which may delay administration of IMP as 
follows: 
• 
Current febrile illness (body temperature ≥38.0°C) or other acute illness within 48 h 
before IMP administration. 
• 
Confirmed SARS-CoV-2 infection; vaccination should still proceed as soon as 
medically indicated but ideally no later than 12 weeks after resolution of any 
serious COVID-19 symptoms at the discretion of the investigator. 
• 
The second Comirnaty injection (injection 2) may also be delayed for medical 
reasons (e.g., influenza vaccination) and such delays should be as short as 
possible, e.g., ≤3 weeks for non-live or attenuated vaccines, ≤5 weeks for live 
attenuated vaccines, ≤12 weeks if SARS-CoV-2 infection is confirmed, etc., with 
the exception of Group B transplant subjects who will receive their injection 2 
based on SRC recommendation. 

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• 
The circumstances leading to the delay and the resulting delay should be 
discussed with the sponsor’s Medical Monitor. 
7.2 
Trial subject discontinuation or withdrawal from the trial 
A trial subject may withdraw from the trial at any time at his/her own request or may be 
discontinued from the trial at any time at the discretion of the investigator for safety, 
behavioral, compliance, or administrative reasons. Withdrawals are expected to be 
uncommon. 
Reasons for discontinuation from the trial include the following: 
• 
Refused further trial procedures 
• 
Lost to follow-up 
• 
Death 
• 
Trial terminated by sponsor 
• 
SAEs thought related to the vaccine 
• 
Trial subject request 
• 
Investigator request 
• 
Important protocol deviation per the investigator after consultation with the Medical 
Monitor 
• 
A Group B transplant subject who receives a non-trial SARS-CoV-2 vaccination 
If the trial subject withdraws consent for data processing, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
For trial subjects who withdraw consent, the investigator must clarify whether consent for 
research sample storage/processing (if given) is also withdrawn. If yes, then they must be 
informed that any research samples collected will be destroyed. The investigator must 
document research sample destruction in the Investigator’s Site File (ISF) and inform the 
sponsor about the withdrawal of consent immediately. 
If possible, permanently discontinued trial subjects will complete all assessments planned 
for the Early Termination Visit. 
7.3 
Lost to follow-up 
A trial subject will be considered lost to follow-up if they repeatedly fail to return for 
scheduled visits and is unable to be contacted by the trial site. 
The following actions must be taken if a trial subject fails to return to the trial site for a 
required trial visit: 
• 
The trial site must attempt to contact the trial subject and reschedule the missed 
visit as soon as possible and counsel the trial subject on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the trial 
subject wishes to continue in the trial. 

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• 
Before a trial subject is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the trial subject (where possible, three 
telephone calls and, if necessary, a certified letter to the trial subject’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the trial subject’s medical record. 
• 
If the trial subject continues to be unreachable, they will be considered to have 
withdrawn from the trial. 
7.4 
Replacement of permanently discontinued trial subjects 
Permanently discontinued trial subjects will not be replaced. 
8 
TRIAL ASSESSMENTS AND PROCEDURES 
Trial subjects must have given informed consent (i.e., have signed the ICF) before 
initiation of any trial-specific procedures are performed. 
See the SoA (Section 1.3) for all planned time points for assessments. 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the trial subject should continue or discontinue 
IMP administration. 
Adherence to the trial protocol requirements, including those specified in the SoA, is 
essential and required for trial conduct. 
All screening evaluations must be completed and reviewed to confirm that potential trial 
subjects meet all eligibility criteria. The investigator will maintain a screening log to record 
details of all trial subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
For the baseline assessments (demographics, medical history), see Section 10.11. 
8.1 
Efficacy assessments 
Not applicable. 
8.2 
Safety assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
The trial site personnel will remind the subject to record the worst grade for each symptom 
in their diary at approximately the same time every evening on the day of IMP injection and 
then every day at the same time until the day of the next planned site visit. The trial site 
personnel will remind the subject to measure their body temperature using the provided 
thermometer and record their body temperature in the diary every day including the day of 
IMP injection. 

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8.2.1 Physical examinations 
Complete physical examinations will be performed at screening. 
Brief physical examinations will be performed at later time points listed in the SoA in 
Section 1.3. 
• 
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. 
• 
A brief (symptom-directed) physical examination. The brief physical examination 
includes an overall health judgment. In-depth physical examinations are required if 
obvious pathological signs are visible or in the case the subject states any signs or 
symptoms. 
8.2.2 Vital signs including body weight 
Body temperature (in °C), pulse rate, respiratory rate, and blood pressure will be assessed 
at the times given in the SoA (Section 1.3). Body temperature will be measured and 
recorded to one decimal place. Body weight (in kg) will also be measured and recorded. 
Blood pressure (systolic/diastolic, in mmHg) and pulse (in bpm) measurements will be 
assessed while the trial subject is in a supine position/at rest. If available, a completely 
automated device should be used, otherwise manual techniques can be used. The same 
method of measurement should be used for the trial subject during the course of the trial. 
Blood pressure and pulse measurements should be preceded by at least 5 min of rest for 
the trial subject in a quiet setting without distractions (e.g., television, cell phones). 
8.2.3 Clinical laboratory tests 
See Section 10.2 for the list of clinical laboratory tests to be performed at baseline and the 
limited times given in the SoA (Section 1.3). 
The investigator must review the laboratory report, document this review with signature 
and date. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the trial should be repeated until the values return to normal or baseline or 
are no longer considered clinically significant by the investigator. 
If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified and the sponsor notified. 
All protocol-required clinical laboratory tests (see Section 10.2) must be conducted in 
accordance with the central laboratory standard. 
If laboratory values from non-protocol-specified laboratory assessments performed at the 
laboratory require a change in trial subject management or are considered clinically 
significant by the investigator (e.g., SAE, AE), then the results must be recorded in the 
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8.2.4 Subject diaries 
For Group A and Group B Immunology Subgroup trial subjects, subject diaries will be 
issued and collected by trial site personnel at the visits given in the SoA (Section 1.3). 
Trial subjects will be asked to record any solicited local reactions at the injection site (pain, 
tenderness, erythema/redness, induration/swelling), and solicited systemic reactions 
(vomiting, diarrhea, headache, fatigue/tiredness, fever [oral temperature of ≥38.0°C], chills, 
nausea, new or worsened muscle pain, new or worsening joint pain). Data will be recorded 
on the reactogenicity CRF, NOT on the AE CRF/log unless the reactogenicity AE extends 
past Day 8. If one of the solicited reactogenicity adverse events from the subject diary 
fulfills SAE criteria, additional CRF SAE data must be provided. 
For Group B transplant subjects, a subject diary should be distributed when they receive 
their second vaccination. 
8.2.5 Assessment of solicited local and systemic reactions 
Group A and Group B Immunology Subgroup trial subjects will be asked to assess their 
local and systemic reactions daily until 7 d after each injection. Trial subject assessments 
will be recorded in the diary provided to the subject by the trial site (Section 1.3). The trial 
site personnel will remind the subject to record in the subject diary the worst grade for 
each symptom every day including the day of IMP injection. 
The reporting on the CRF of local and systemic reactions will be based on the subject’s 
assessments only. Reactions will be graded based on the guidance given in the FDA 
Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials” (see Section 10.3.2). 
8.2.6 Subject hotline 
Trial subjects will be provided with contact details for a Subject hotline, which can be used 
to contact the trial site during their participation in the trial should they require guidance or 
should they experience any symptoms of illness. The reporting of any symptoms of illness, 
e.g., flu-like symptoms, may trigger diagnostic measures (including ad hoc site visits) at 
the discretion of the investigator. 
For guidance on the handling of specific adverse reactions, see Section 8.5. 
8.2.7 
Oral swabs for NAAT-based SARS-CoV-2 testing for screening 
and surveillance 
Oral swabs for (nucleic acid amplification-based test [NAAT]-based) SARS-CoV-2 testing 
will be collected by trial site personnel at the time points provided in the SoA (Section 1.3). 
For screening (Visit 0 on Day-1 or pre-dose on Day 1), the NAAT-based analysis of oral 
swabs for SARS-CoV-2 can be performed by either a central laboratory or a “point of care” 
device at the trial site or a local laboratory of the trial site to ensure rapid results. 
• 
If a central laboratory is used: Only the SARS-CoV-2 status will be tested and no 
further data will be generated. 

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• 
If a point of care device is used: The most commonly used devices eventually 
come with pre-defined test panels that test for a range of pathogens and not just 
for SARS-CoV-2. Thus, inevitably and automatically, incidental data for the 
pathogens other than SARS-CoV-2 will be generated when using such devices. 
Since this incidental data is not required by this trial, only the results for SARS-
CoV-2 will be recorded in the CRF, analyzed, and reported as described in this 
protocol. If a test result for SARS-CoV-2 or another pathogen must be reported to 
relevant authorities, this notification will be done by the trial site. 
For surveillance (Visits 2 and later), the NAAT-based analysis of oral swabs for SARS-
CoV-2 will be conducted in the central laboratory. 
Additionally, any potentially SARS-CoV-2 - infected and symptomatic trial subjects will be 
asked to return to the site for SARS-CoV-2 diagnostics as soon as possible. Oral swabs 
for SARS-CoV-2 genomic sequencing will also be collected and analyzed at a later time 
point. If subject tests SARS-CoV-2 positive outside of the trial site, then the site will 
request the information from the subject. 
Instructions on the sample handling and shipping to the analysis site will be provided in a 
Laboratory Manual. The methodology used for the NAAT-based analysis will be 
documented in the Biomarker Manual. 
8.2.8 
Serum for nucleocapsid protein testing 
Blood will be drawn by trial site personnel for nucleocapsid ELISA SARS-CoV-2 testing at 
the time points provided in the SoA (Section 1.3); this will use blood draw for Neutralizing 
antibody titers and antibody binding (NATAB) (see Section 8.10.1). 
Nucleocapsid ELISA SARS-CoV-2 testing will be performed at a central laboratory. 
8.2.9 
Triggered SARS-CoV-2 genomic sequencing 
Swabs for triggered SARS-CoV-2 genomic sequencing storage will be collected by trial 
site personnel at the time points provided in SoA (Section 1.3). 
The swabs will be inserted into collection tubes pre-filled with RNAlater stabilizer solution. 
The swabs must be stored in the central laboratory at a minimum -70°C until the end of the 
trial. 
There are two triggers for SARS-CoV-2 genomic sequencing: 
• 
Serum-based nucleocapsid ELISA SARS-CoV-2 testing using one of the samples 
collected for NATAB. 
• 
Oral swab-based NAAT testing for surveillance conducted in the central laboratory. 
SARS-CoV-2 genomic sequencing will be initiated if any of the above tests are positive 
(with or without symptoms). 
Instructions on the sample handling and shipping to the analysis site will be provided in a 
Laboratory Manual. The methodology used for these assessments will be documented in 
the Biomarker Manual. 

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The outcome of triggered SARS-CoV-2 genomic sequencing would be SARS-CoV-2 
S antigen sequences and/or whole genome sequences and assigned (where possible) to 
known viral variants. 
8.3 
Adverse events and serious adverse events 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE or AESI and are responsible 
for following up all AEs and SAEs. 
The detection of AE or SAE or AESI is unsolicited. 
Solicited AEs that are recorded from the subject diaries on the reactogenicity CRFs should 
not be reported as AEs unless the solicited AE meets criteria for SAE or begins after Day 8 
or started before Day 8 and continues past Day 8. 
8.3.1 Time period and frequency for collecting AE, AESI, and SAE 
information 
For trial subjects enrolled in this clinical trial, i.e., after transfer from the parent trial to this 
trial, all AEs, AESI, and SAEs (including a death) will be recorded at the time points listed 
in the SoA in Section 1.3. All safety reporting will occur through this rollover trial; this 
includes the reporting of non-vaccine related AEs that are unresolved from the parent trial. 
For subjects who receive a non-trial SARS-CoV-2 vaccination, AEs/SAEs will be collected 
as specified above until the date when the subject was vaccinated with the non-trial 
SARS-CoV-2 vaccine. The AEs expected to be captured after non-trial SARS-CoV-2 
vaccination are within the frame of post-marketing safety data reporting. 
Investigators are not obligated to actively seek AEs or SAEs at any time after a trial 
subject has been discharged from the trial, however, if the investigator learns of any SAE 
(including a death), that they consider to be reasonably related to the IMP administration 
or trial participation, the investigator must promptly notify the sponsor. 
8.3.2 Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and 
non-leading verbal questioning of the trial subject is the preferred method to inquire about 
AE occurrences. 
8.3.3 Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each trial 
subject at subsequent visits/contacts. All AEs/SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the trial subject is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is provided in 
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The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other healthcare professionals. 
New or updated information will be recorded in the originally completed CRF. 
The investigator must submit any updated SAE data to the sponsor within 24 h of receipt 
of the information as indicated in Section 10.3.1.10. 
All ongoing AEs/SAEs will be followed until resolution, considered by the investigator to be 
stable or chronic (resolved with sequelae), the trial subject is lost to follow-up or the trial 
subject withdraws consent. If no final status is reached by the time the trial subject is 
discharged from the trial, the investigator must confirm the unavailability of a final status. 
8.3.4 Regulatory reporting requirements for SAEs 
Prompt notification of an SAE by the investigator to the sponsor is essential so that legal 
obligations and ethical responsibilities for the safety of trial subjects and the safety of a trial 
treatment under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IECs, and investigators. The execution of expedited 
reporting to the different entities may be delegated as detailed in the trial Safety 
Management Plan. 
Safety reports will be prepared for suspected unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
For the IMP, it is the sponsor’s or delegate’s responsibility to perform SUSAR reporting to 
the regulatory authority, the IEC, and the other investigators as required by national law 
and applicable guidelines. 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor should 
review it and then file it together with the IB. If required by local requirements, the 
investigator will notify the relevant IEC. 
8.3.5 Pregnancy 
For WOCBP, pregnancy tests will be performed using commercial kits at the times given in 
the SoA (see Section 1.3). 
Pregnancy information (information on trials subjects who become pregnant or information 
for female partners of male trial subjects who become pregnant) will be collected for 
pregnancies that occurred after the date of the first injection of IMP until the subject 
terminates or completes the study. 

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Pregnancy information will only be collected after obtaining written informed consent from 
the pregnant female subject (or if a male subjects’ partner becomes pregnant, written 
informed consent from both). 
If a pregnancy is reported, the investigator should inform the sponsor within 24 h of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 Death events 
Any death that occurs within the observation period will be reported as an SAE. 
In case of a fatal event, the event term should not be “death” but the underlying event 
which led to death (death = outcome). If there is more than one AE in a fatal case, only for 
the AE leading to death the outcome “fatal” should be selected. If the cause of death is 
unknown and cannot be ascertained at the time of reporting, “unexplained death” should 
be documented as event term. 
8.3.7 Disease-related events/outcomes not qualifying as AEs or SAEs 
Not applicable. 
8.3.8 Adverse events of special interest 
The following will be reported as AESIs: 
• 
Myocarditis (all Levels of Certainty including ‘’Possible cases’’ (1 to 3) as per 
Brighton Collaboration Case Definition) 1 to 3 (Possible case), 
Myocarditis_Version_1.0_15 July 2021_FINAL_for Posting) 
• 
Pericarditis (all Levels of Certainty including ‘’Possible cases’’ (1 to 3) as per 
Brighton Collaboration Case Definition) 1 to 3 (Possible case), 
Pericarditis_Version_1.0_15 July 2021_FINAL_for Posting) 
• 
Anaphylaxis 
• 
Thromboembolic events (e.g., deep vein thrombosis, stroke, myocardial infarction) 
• 
Immune thrombocytopenia 
• 
Immune based neurologic events (e.g., optic neuropathy, Guillain-Barré syndrome) 
8.4 
Treatment of overdose 
Any dose of trial treatment above the planned doses specified in this protocol will be 
considered an overdose. In the event of overdose: 
• 
Closely monitor the trial subject for any AE/SAE and laboratory abnormalities (at 
least for 7 d). 
• 
(At the discretion of the investigator) Give symptomatic treatment. 

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• 
Inform the sponsor’s Medical Monitor as soon as possible; the sponsor’s Medical 
Monitor should agree with the investigator regarding any action triggered, e.g., trial 
subject withdrawal from the trial or (if applicable) trial treatment. 
• 
Document the quantity of the excess dose overdose in the CRF. 
8.5 
Treatments for specific adverse reactions 
The adverse reactions determined for Comirnaty from the available unblinded clinical trial 
data (from BNT162-02/C4591001 [NCT04368728]) are mostly reflective of mild to 
moderate local and systemic reactogenicity events. The most frequent adverse reactions 
in trial subjects 16 yrs of age and older were injection site pain, fatigue, headache, myalgia 
and chills, arthralgia, pyrexia and injection site swelling, and were usually mild or moderate 
in intensity and resolved within a few days after vaccination. Additional adverse reactions 
determined from the clinical trial data are lymphadenopathy, nausea and malaise. Since 
authorization of Comirnaty, anaphylaxis has been reported and determined to be an 
adverse reaction. For details see the BNT162 IB. 
Treatment of these adverse reactions is at the discretion of the investigators, however, the 
following suggestions are provided: 
• 
After the first occurrence of flu-like symptomatology including fever, subjects can 
be treated with standard therapeutic dose of acetaminophen (preferable), or a 
nonsteroidal anti-inflammatory drug if acetaminophen is contraindicated. 
• 
Corticosteroids should be avoided as either prophylaxis or treatment as it 
counteracts the effects of immunization. 
• 
Ensure adequate hydration of trial subjects on the day of immunization. Consider 
administering fluids (e.g., water for drinking, 0.5 to 1.0 L) within ~2 h following the 
immunization per trial site standard. 
If subjects experience enhanced respiratory disease symptom kinetics that are 
inconsistent with a relationship to RNA immunization, additional diagnostic measures 
should be considered, and the Medical Monitor should be informed. 
If subjects report symptoms that could represent myocarditis or pericarditis, in addition to 
any medically indicated evaluations at the discretion of the investigators, the following 
United States Center for Disease Control (CDC) clinical recommendations for myocarditis 
and pericarditis following COVID-19 vaccination published on 28 May 2021 
(https://www.cdc.gov/vaccines/covid-19/clinical-considerations/myocarditis.html) should be 
considered: 
• 
For initial evaluation, consider an ECG, troponin level, and inflammatory markers 
such as C-reactive protein and erythrocyte sedimentation rate. In the setting of 
normal ECG, troponin, and inflammatory markers, myocarditis or pericarditis are 
unlikely. 
• 
Consider consultation with: 
o Cardiology for assistance with cardiac evaluation and management. 
o Infectious disease and/or rheumatology to assist in this evaluation. 

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• 
Where available, evaluate for potential etiologies of myocarditis and pericarditis, 
particularly acute COVID-19 infection (e.g., PCR testing), prior SARS-CoV-2 
infection (e.g., detection of SARS-CoV-2 nucleocapsid-binding antibodies), and 
other viral etiologies (e.g., enterovirus PCR and comprehensive respiratory viral 
pathogen testing). 
8.6 
Safety stopping criteria 
The SRC will review and evaluate the collected safety data for Group A and all reported 
SAEs from the trial at a minimum every 16 weeks during the trial and any emerging data 
concerns from Group B (e.g., SUSARs, Group B transplant data, etc.). A decision to stop 
treatment for an individual subject or to terminate the trial may be taken by the sponsor 
and investigator if safety concerns are identified by the SRC. 
All SAEs will be reviewed by the SRC and all SUSARs as soon as possible. Any trial SAE 
but specifically a SUSAR in Group A may trigger a temporary stop of IMP administration to 
new subjects in Group A until the SRC has reviewed and discussed the relevant data and 
come to a recommendation to continue or permanently stop trial injections for Group A. 
8.7 
Pharmacokinetics 
Not applicable. 
8.8 
Pharmacodynamics 
Not applicable. 
8.9 
Genetics 
After completion of the planned investigations of the immune response, residual blood 
and/or isolated PBMCs may be used for genetic analysis. 
If not already done as part of the parent trial, blood and/or isolated PBMCs may be used 
for human leukocyte antigen (HLA) typing of a subject to allow additional analysis, e.g., 
characterization of T-cell receptor (TCR) repertoire and/or phenotypic characterization of 
antigen-specific T cells. Data generated with these additional analyses may provide 
information about the HLA dependency of immune response (e.g., if distinct HLA types 
have stronger/better immune response towards SARS-CoV-2). 
Further, residual blood may also be used for profiling (e.g., by use of next generation 
sequencing) of B-cell receptor (BCR) and/or TCR variants in peripheral blood after 
vaccination. 
Blood samples will only be used for genetic analysis if the trial subjects have provided 
separate informed consent for this genetic analysis. 
8.10 
Immune responses 
Neutralizing antibody titers, antibody binding and CMI will be assessed at the times listed 
in the SoA (Section 1.3). 

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Instructions on the sample collection, handling, and shipping will be provided in a 
Laboratory Manual. The methodology used for these assessments will be documented in 
the Biomarker Manual. 
Leftover blood after completion of the serology assessments will be used for the analyses 
as described in Section 8.10.3 (i.e., for explorative biomarker/immunogenicity research 
purposes). 
Trial subjects will be asked if leftover blood may also be used for research purposes, e.g., 
to develop methods, assays, etc., related to BNT162 vaccine candidates. The use of 
leftover blood for these purposes will require a separate informed consent. 
8.10.1 
Neutralizing antibody titers and antibody binding (NATAB) 
Neutralizing antibody titers and antibody binding assessment comprise of: 
• 
A functional antibody titer, e.g., VNT or an equivalent assay (e.g., pVNT assay). 
o Seronegative is defined as titers below the starting dilution (i.e., below the 
limit of detection of the assay). 
• 
Seroconversion after immunization is defined as a 4-fold increase in titer. 
o for seronegative pre-immunization sera: a titer ≥ 4-times the limit of 
detection. 
o for seropositive pre-immunization sera: a titer which is 4-fold higher than the 
measured pre-immunization titer. 
• 
An antibody binding assay, e.g., ELISA or an equivalent assay. 
o Seroconversion after immunization is defined as a 4-fold increase in 
titer/antibody concentration. 
8.10.2 
Cell mediated immune responses 
Cell mediated immune responses assessments comprise: 
• 
CMI/responses mediated by immune cells such as CD4 and CD8 T cells and their 
functional phenotypic subset by, e.g., ELISpot, ICS, multimer analyses, cytokine 
secretion assays, flow cytometry, and other tests. 
• 
CMI analysis will include among others CD4 and CD8 T cells, Th1-specific 
cytokines (e.g., IFN-gamma, TNF-alpha, IL-2, or IL-12) and Th2-specific cytokines 
(e.g., IL-4, IL-5, IL-10, IL-13) to analyze the induction of either balanced Th1/Th2 
responses, or of unbalanced Th1-dominant or Th2-dominant immune responses, 
respectively. 
8.10.3 
Explorative biomarker/immunogenicity research 
After completion of the planned investigations of the immune response, residual blood 
samples may be used for explorative biomarker/immunogenicity research. 
This research may include investigation of vaccine-induced immune responses by use of, 
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T cells (e.g., by flow cytometry-based phenotyping including multimer staining), analysis of 
BCR/TCR repertoire (e.g., by next generation sequencing) and multiplex-cytokine analysis. 
In addition, residual blood samples may be stored and analysis may be performed on 
biomarker variants thought to play a role in the mechanism of action of BNT162 vaccine 
candidates to evaluate their association with observed clinical responses to BNT162 
vaccine candidates 
Samples for research will be retained for use for up to 5 years after the end of the trial. 
Subjects will be informed about biosample storage and consent will be obtained. The tube 
with the sample will be labeled with a number (optionally also with a bar code) to keep the 
subject’s identity confidential; the tube label will not include information that could be used 
to identify the subject. Results of the analyses will be linked to the clinical information 
collected during the trial using this specific number. The analysis will only be carried out on 
the basis of the label data and samples. Research samples and all data generated using 
the samples, will be handled in accordance with applicable laws and regulations; this 
includes requirements applicable for data protection, for sample shipment outside 
Germany, and a potential withdrawal of consent. 
8.11 
Blood collection 
Up to ~615 mL (Group A) or ~620 mL (Immunology Subgroup of Group B) or ~120 mL 
(Group B no additional CMI or reactogenicity assessments) blood will be drawn per subject 
over the course of the trial. In the first 7 to 8 weeks, a maximum of 390 mL amount of 
blood is drawn in any group. 
Additional blood samples may be taken, e.g., for safety assessments after AEs or SAEs. 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical hypotheses 
There is no formal statistical hypothesis under test. 
9.2 
Sample size determination 
No formal sample size calculations were performed as this rollover trial is based on the 
trials BNT162-01 and BNT162-04. 
9.3 
Analysis sets 
The following analyses sets are defined: 
Analysis set 
Description 
Screened Set 
All subjects who signed informed consent. 
Safety Set 
All subjects who received at least one dose of IMP. 
Immunogenicity Set 
(IMM) 
All subjects who received at least one dose of IMP and have at least one post-
baseline functional antibody titer immunogenicity assessment. 

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Analysis set 
Description 
Immunogenicity Per-
Protocol set (IMMPP) 
All subjects included in the IMM set that have no major protocol deviations as 
determined by the clinician. 
 
9.4 
Statistical analyses 
Statistical analyses will be performed by BioNTech or a designated Contract Research 
Organization (CRO). All statistical analyses will be carried out using SAS®, Version 9.3 or 
higher, and/or other statistical software as required. 
The statistical analysis plan (SAP) will be finalized prior to database snapshot for the 
primary analysis and it will include a more technical and detailed description of the 
statistical analyses described in this section. Any deviations from the planned analyses 
described in the final SAP will be described and justified in the clinical trial report. 
This section gives a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints. 
9.4.1 General considerations 
In general, data will be summarized by groups (i.e., two randomized subgroups in Group A 
and non-randomized Group B with an immunology subset). Data may be pooled with trials 
BNT162-01 and BNT162-04. 
Continuous variables will be summarized by group using the following descriptive 
statistics: number of subjects (n), mean, standard deviation, median, minimum, and 
maximum. 
Categorical variables will be summarized by group presenting absolute and relative 
frequencies (n and %) of subjects in each category. 
Baseline is defined as last available value prior to first dose of IMP. 
9.4.2 Primary endpoints 
The primary endpoints are defined in Section 3. 
All AEs will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA®) coding system to get a system organ class (SOC) and preferred 
term (PT) for each AE. 
Reactogenicity 
Solicited local and systemic reactions (from the subject diary) will be summarized using 
the Safety Set. In general, solicited reactions will be analyzed for each immunization, i.e.: 
• 
Up to 7 d after each IMP injection 
For each injection, the number and percentage of subjects reporting at least one local 
reaction or systemic reaction (i.e., solicited data collected using subject diaries) will be 
summarized for each of the following types using the Safety Set: 

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• 
Any local reactions or systemic reactions 
• 
Grade ≥3 local reactions or systemic reactions 
Moreover, the number and percentage of subjects reporting at least one local reaction will 
be summarized by worst grade using the Safety Set. 
Unsolicited TEAEs 
For Group A and Group B immunology subset, the number and percentage of subjects 
reporting at least one TEAE (defined in Section 10.3.1) will be summarized by PT nested 
within SOC for each of the following AE types using the Safety Set: 
• 
Any AE 
• 
Related AE 
• 
Grade of AE 
• 
Related Grade ≥3 AE 
• 
Any solicited AE that continues past 7 d post-trial injection or is an SAE, or AE that 
fits the definition of a solicited AE but starts after Day 8 
• 
Any SAE 
• 
Related SAE 
• 
AESI 
Moreover, the number and percentage of subjects with any AE will be summarized by 
worst grade by PT nested within SOC. 
For Group B, AESIs and SAEs will be analyzed. 
Additional AE analyses may be described in the SAP. 
9.4.3 Secondary endpoints 
The secondary endpoints are defined in Section 3. 
All secondary immunogenicity analyses will be performed first with the IMM population 
(see Section 9.3) as this is an exploratory hypothesis-generating trial. However, the 
Immunogenicity Per Protocol set (IMMPP) population will also be analyzed. 
The scheduled time points for assessment are given in the SoA (see Section 1.3). 
The binary secondary endpoints will be summarized by group presenting absolute and 
relative frequencies (n and %) of subjects in each category for each assessment. The 
continuous secondary endpoints will be summarized by group using summary statistics. 
For each subject and each time point, antibody titers will be defined based on the 
calculated geometric mean of antibody titers assessed in duplicate. Additionally, GMT with 
95% CI will be presented. 
Change in antibody titers to recombinant S1 and RBD protein derived from reference and 
B.1.351 strains will be assessed from baseline to time points as identified in the endpoints 
(see Section 3) and SoA (see Section 1.3). In addition to analysis of changes in 

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neutralizing antibody and binding antibody titers, functional cross-neutralization of vaccine-
induced antibodies to B.1.351 in relationship to reference strain will be analyzed at time 
points identified in the secondary endpoints. 
9.4.4 Exploratory endpoints 
The exploratory endpoints are defined in Section 3. Exploratory analyses will be described 
in the SAP. 
9.4.5 Other safety analyses 
Safety data other than AEs that will be summarized includes clinical laboratory parameters 
and vital signs for Group A and the Immunology Subgroup of Group B only. All safety 
analyses will be based on the Safety Set and will be summarized descriptively by group 
unless otherwise stated. 
Clinical laboratory parameters for Group A and the Immunology Subgroup of 
Group B  
The clinical laboratory parameters to be summarized and assessed for Group A and the 
Immunology Subgroup of Group B are listed in Section 10.2. The scheduled time points for 
assessment are given in the SoA (see Section 1.3). 
Clinical laboratory parameters at each time point and change from baseline to each post-
baseline time point will be summarized using descriptive summary statistics for each 
parameter by group. 
Shift tables from baseline to worst intensity grade will be provided for each laboratory 
parameter by group. 
Additionally, the occurrence of clinically significant abnormal laboratory results within a trial 
subject will be analyzed using descriptive summary statistics for each parameter and visit 
by group. 
Abnormal laboratory results will be graded using criteria based on the guidance given in 
FDA Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” (see Section 10.3.2). 
Laboratory parameter results will be listed along with the normal ranges. Values that are 
below or above the normal ranges will be flagged. 
Clinical laboratory analysis details will be described in the SAP. 
Vital signs for Group A and the Immunology Subgroup of Group B 
The vital sign parameters to be summarized and assessed are given in Section 8.2.2. The 
scheduled time points for assessment are given in the SoA (see Section 1.3). 
Vital sign parameters at each time point and change from baseline to each post-baseline 
time point will be summarized using descriptive summary statistics for each parameter by 
group. 

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9.4.6 Other analyses 
Other analyses will be described in the SAP. 
9.5 
Interim analyses 
No formal interim statistical analysis will be performed. However, preliminary analyses may 
be performed after completion of Visit 5 for any group (i.e., Group A or Group B). 
9.6 
Data monitoring committee 
No Data Monitoring Committee is planned. An SRC is planned, for details see 
Section 10.1.5. 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Regulatory, ethical, and trial oversight considerations 
This trial will be conducted in according to this protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, Good Clinical Practice (GCP), and applicable 
regulatory requirements. 
10.1.1 Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• 
Applicable GCP Guidelines 
• 
Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IEC and reviewed and approved by the IEC 
before the trial is initiated. 
Any amendments to the protocol will require IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate 
hazard to trial subjects. 
The coordinating investigator or delegate will be responsible for the following: 
• 
Providing written summaries of the status of the trial to the IEC annually or more 
frequently in accordance with the requirements, policies, and procedures 
established by the IEC. 
• 
Notifying the IEC of SAEs or other significant safety findings as required by IEC 
procedures. 

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• 
Providing oversight of the conduct of the trial at the site and adherence to 
requirements of ICH guidelines, the IEC, European regulation 536/2014 (if 
applicable), and all other applicable local regulations. 
The principal investigator, any investigator(s), the sponsor, or personnel at other 
establishments must cooperate with any inspection of the documents, facilities, records, 
and other resources deemed appropriate by the inspecting authorities to be related to the 
trial and that may be located at the trial site, at the sponsor, or at other establishments. 
The sponsor must be notified as soon as possible about any upcoming regulatory authority 
inspection. 
10.1.2 Financial disclosure 
All investigators will provide the sponsor with sufficient, accurate financial information as 
requested to allow the sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and 
for 1 year after completion of the trial. 
10.1.3 Informed consent process 
Informed consent must be obtained before any trial-specific screening procedure is 
performed. 
Trial subjects must be informed that their participation is voluntary. 
The investigator or his/her representative will explain the nature of the trial to the trial 
subject and answer all questions regarding the trial. 
Trial subjects will be required to sign a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IEC or trial site. 
The medical record must include a statement that written informed consent was obtained 
before the trial subject was enrolled in the trial and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
Trial subjects must be informed in a timely manner if new information becomes available 
that may impact their willingness to participate in the trial. If required, subjects will be re-
consented to updated written information and consent forms. 
Separate informed consent will be obtained for the use of samples for genetics, i.e., testing 
of HLA type, BCR and TCR variants (see Section 8.9), and for the use of leftover blood for 
research purposes e.g., to develop methods, assays, etc. (see Section 8.10). 
10.1.4 Data protection 
Trial subjects will be assigned a unique identifier by the investigator according to the 
sponsor specifications on unique identifier assignment. Any trial subject records or 
datasets that are transferred to the sponsor will contain the identifier only; trial subject 

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names or any information which would make the trial subject identifiable will not be 
transferred. 
Trial subjects must be informed that his/her personal trial-related data will be used by the 
sponsor in accordance with local data protection laws. The level of disclosure must also be 
explained to the trial subject who will be required to give consent for their data to be used 
as described in the informed consent. 
Trial subjects who withdraw consent must be informed that the data collected up until 
consent was withdrawn will still be used by the sponsor as described in the ICF. 
Trial subjects must be informed that their medical records may be examined by sponsor 
quality assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IEC members, and by inspectors from regulatory authorities. 
10.1.5 Committees - SRC 
Safety reviews of the unblinded data will be conducted by an SRC every 16 weeks and 
ad hoc basis. The SRC will review all safety data, including AESIs, and SAEs, as well as 
laboratory data and other relevant safety data. 
The SRC will be constituted and act according to written procedures described in a 
charter. The SRC will prepare written minutes of its meetings. 
The SRC will at least comprise a sponsor medical representative, the Medical Monitor, a 
statistician, coordinating investigator, a sponsor-independent investigator, and on an 
ad hoc basis, a representative for the respective trial site depending on the trial subject in 
question. 
10.1.6 Dissemination of clinical trial data 
A final clinical trial report integrating all trial results will be prepared by the sponsor. 
This clinical trial will be registered and trial results be posted on publicly accessible trial 
registries (e.g., the EU Clinical Trial Register) in accordance with the applicable 
regulations. 
10.1.7 Data quality assurance 
All trial subject data relating to the trial will be recorded in a CRF unless transmitted to the 
sponsor or designee electronically (e.g., laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit trial-related monitoring, audits, IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality, 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities and requirements, including handling of non-compliance issues 

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and monitoring techniques (central, remote, or on site monitoring) are provided in the 
Monitoring Plan. 
The sponsor or designee is responsible for the data management of this trial including 
quality checking of the data. 
The sponsor assumes accountability for actions delegated to other parties (e.g., CRO). 
Trial monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of trial subjects are being protected; and that 
the trial is being conducted in accordance with the currently approved protocol and any 
other trial agreements, GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this trial must 
be retained by the investigator for 25 years after trial completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
10.1.8 Source documents 
Source documents including subject diaries provide evidence for the existence of the trial 
subject and substantiate the integrity of the data collected. Source documents are filed in 
the ISF. 
Source documents are original documents, data, and records (e.g., hospital records, 
clinical and office charts, laboratory notes, memorandums, subject diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy, at the laboratories and at medico-technical departments involved in 
the clinical trial). 
Data entered in the CRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the trial. Also, 
current medical records must be available. 
Source data are all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents 
(original records or certified copies). 
10.1.9 Trial and site start and closure 
The trial start date is the date on which the trial will be open for enrollment of trial subjects 
at any site. 
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The sponsor reserves the right to close the trial site or terminate the trial or a group within 
the trial at any time for any reason at the sole discretion of the sponsor. Trial sites will be 
closed upon trial completion. A trial site is considered closed when all required documents 
and trial supplies have been collected and a trial site closure visit has been performed. 
The investigator may initiate trial site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by the sponsor or investigator may include but 
are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines. 
• 
Inadequate recruitment of trial subjects by the investigator. 
• 
Discontinuation of further trial treatment development. 
If the trial is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs, the regulatory authorities, and any CROs used in the trial of the 
reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the trial subject and should assure 
appropriate follow-up. 
10.1.10 
Publication policy 
The results of this trial may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This will allow the sponsor to protect proprietary information and to 
provide comments. 
The sponsor will comply with the requirements for the publication of trial results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multi-site trials only in their entirety and not as individual site data. In this 
case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors (ICMJE) authorship requirements. 
10.1.11 
Protocol preparation and approval 
This protocol has been prepared, reviewed and approved, including wet ink sign-off by the 
sponsor’s responsible person, in accordance with the sponsor’s standard operating 
procedures. Documentation of this process is filed in the Trial Master File. 
10.2 
Clinical laboratory tests 
Blood and urine will be collected for clinical laboratory tests at the times given in the SoA 
(Section 1.3). 

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Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count and differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count. 
Clinical chemistry 
Alkaline phosphatase, creatinine, ferritin, C-reactive protein, albumin, alanine 
aminotransferase, amylase, aspartate aminotransferase, gamma glutamyl transpeptidase, 
total bilirubin, blood urea nitrogen, glucose, lipase, sodium, potassium, calcium. 
FSH: Only in women who are not of childbearing potential. 
Urinalysis 
Dipstick: glucose, bilirubin, ketone, specific gravity (1 mL ≙ 1 g), blood, pH, protein, 
urobilinogen, nitrite, and leukocytes. 
Microscopic urinalysis: If warranted by dipstick results, urine sediment will be 
microscopically examined for presence of red blood cells, white blood cells, casts, crystals, 
epithelial cells, and bacteria. 
10.3 
Adverse events: Definitions and procedures for recording, 
evaluating, follow-up, and reporting 
10.3.1 Definition of AE and TEAE 
• 
An AE is any untoward medical occurrence in a trial subject, temporally associated 
with the use of trial treatment, whether or not considered related to the IMP. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding that is clinically significant), symptom, or disease (new 
or exacerbated) temporally associated with the use of IMP. 
• 
Events after signing ICF and before IMP administration will be handled as AEs 
(also called pre-existing conditions). 
• 
A TEAE is defined as any AE with an onset after the first IMP injection or worsened 
after the first IMP injection (if the AE was present before the first administration of 
IMP). AEs with an onset date more than 28 d after the last administration of IMP 
will be considered as treatment-emergent only if assessed as related to IMP by the 
investigator. 
10.3.1.1 
Events meeting the AE definition 
• 
Any abnormal laboratory test results or other safety assessments (e.g., vital signs 
measurements), including those that worsen from baseline, and which are 
considered clinically significant in the medical and scientific judgment of the 
investigator, may be considered as AEs. 
• 
New conditions or (at the discretion of the investigator) any worsening of a pre-
existing condition detected or diagnosed after Visit 0. 

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• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either trial 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE. 
10.3.1.2 
Events not meeting the AE definition 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
10.3.1.3 
Suspected adverse reaction 
All untoward and unintended responses to an IMP-related to any dose administered. 
• 
The definition also covers medication errors and uses outside what is foreseen in 
the protocol, including misuse and abuse of the IMP. 
• 
The definition implies a reasonable possibility of a causal relationship between the 
event and the IMP. This means that there are facts (evidence) or arguments to 
suggest a causal relationship and an alternative etiology is not apparent. 
10.3.1.4 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose: 
• 
Results in death. 
• 
Is life-threatening. 
• 
The term “life-threatening” in the definition of “serious” refers to an event in which 
the trial 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. 
• 
Requires trial subject hospitalization or prolongation of existing hospitalization. 
• 
In general, hospitalization signifies that the trial subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or out trial subject setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
• 
Results in persistent disability/incapacity. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 

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• 
Is a congenital anomaly or a birth defect. 
• 
Other situations: 
o Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events 
that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the trial subject or may require medical or surgical 
treatment to prevent one of the other outcomes listed in the above definition. 
These events should usually be considered serious. 
10.3.1.5 
Suspected unexpected serious adverse reactions 
All suspected adverse reactions related to an IMP that occur in this trial and that are both 
unexpected and serious are SUSARs. SUSARs are subject to expedited reporting. 
10.3.1.6 
Use of the terms “severe” and “serious” 
Severity (intensity or grade) and seriousness need to be assessed independently for each 
AE and be recorded in the CRF. For a definition of the terms “severe” and “serious” for 
AEs, see: 
• 
Section 10.3.1.7 for AEs. 
• 
Section 10.3.1.4 for SAEs (see Section 10.3.1.10 for SAE reporting instructions). 
10.3.1.7 
Recording and follow-up of AE and/or SAE 
AE and SAE recording 
The investigator needs to assess and document any AE regardless of association with the 
use of the trial treatment during the period of observation as defined in Section 8.3.1. 
Data pertaining to AEs will be collected during each trial visit and the clinical significance 
of any sign or symptom needs to be evaluated by the investigator. 
• 
Clinically significant findings need to be documented as AEs in the source data and 
CRF. Findings that are evaluated and documented in the source data as not 
clinically significant (e.g., an abnormal laboratory value without any clinical 
manifestation), should not be documented as AE. 
• 
AEs that are related to one clinical event should be subsumed under that event 
when recorded on the CRF. For example, elevated creatinine, nausea, vomiting, 
hypercalcemia should be subsumed under renal failure if that explains the etiology 
for the subsumed signs and symptoms. 
• 
The investigator will then record AE information in the CRF and perform an 
assessment on: 
o Intensity, see the section “Assessment of intensity” in Section 10.3.2 for 
guidance on the assessment of intensity, 
o Seriousness, 

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o Outcome, 
o Causal relationship of the AE to the trial treatment, 
o Any trial treatment action and/or any other action taken. 
• 
All assessments as well as AE term (diagnosis/description), start date and time of 
onset, end date and time need to be documented in the CRF. 
• 
There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all trial subject identifiers, with the 
exception of the trial subject number, will be redacted on the copies of the medical 
records before submission to the sponsor. 
• 
To avoid colloquial expressions, the AE should be reported in standard medical 
terminology. The investigator will attempt to establish a diagnosis of the event 
based on signs, symptoms, and/or other clinical information. Whenever possible, 
the diagnosis (not the individual signs/symptoms) will be documented as the AE. If 
a definitive diagnosis is not possible, the individual signs and symptoms should be 
recorded. 
Assessment of AE and/or SAE intensity 
The assessment of AE and/or SAE intensity should be done consistently for all subjects 
treated with the same treatment and dose. In case of doubt, the Medical Monitor should be 
consulted. 
The intensity of AEs or SAEs will be graded by the investigator. For further guidance 
please refer to the FDA Guidance for Industry “Toxicity Grading Scale for Healthy Adult 
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials”. Where specific 
guidance for an adverse event term is not provided, the following general approach should 
be followed: 
• 
Grade 1 - Mild; does not interfere with the subject’s usual function. 
• 
Grade 2 - Moderate; interferes to some extend with the subject’s usual function. 
• 
Grade 3 - Severe; interferes significantly with the subject’s usual function. 
• 
Grade 4 - Potentially life-threatening; life-threatening consequences, urgent 
intervention required. 
Please also refer to the intensity tables given in the guideline for intensity of clinical and 
laboratory abnormalities to be reported as AEs: 
• 
Guideline Section III.A for assessment of clinical abnormalities (local and systemic) 
Actions taken by the investigator 
Actions taken by the investigator as a result of an AE must be documented. 
Action(s) taken with trial treatment (IMPs) by the investigator: 
• 
Dose not changed (= continuation of trial treatment administration according to the 
trial protocol) 

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• 
Drug withdrawn 
• 
Not applicable (e.g., in case treatment with trial treatment has not yet started or 
event starts after last trial treatment administration) 
Other action(s) that may be taken by the investigator include: 
• 
None 
• 
Remedial drug therapy 
• 
Other specific treatment(s) of AE (to be specified) 
Outcome 
The investigator has to assess the outcome of an AE (and not the trial subject’s outcome) 
at the time of documentation based on the following criteria: 
• 
Recovered/resolved* (= complete resolution of the AE) 
• 
Recovering/resolving (= AEs which are improving but not yet resolved completely, 
e.g., decrease in an intensity grade) 
• 
Not recovered/not resolved (= AEs which are ongoing without improving or still 
present when the trial subject deceases due to another cause) 
• 
Recovered/resolved with sequelae* (= trial subject recuperated but retained 
pathological conditions resulting from the AE; the sequelae should be indicated) 
• 
Fatal** (= death due to the AE) 
• 
Unknown (e.g., in case the trial subject is lost to follow-up) 
* Generally, an AE is defined as recovered/resolved if all symptoms have ceased, no 
medication for treatment of the event is taken anymore and no other measures (e.g., 
hospitalization) are ongoing. 
If the trial subject has developed permanent or chronic symptoms or if the event requires 
long term medication(s), the AE is defined as recovered/resolved with sequelae as soon 
as no changes of symptoms and/or medication(s) are expected anymore. 
An AE that is documented as a worsening of a medical condition already known at 
baseline, is defined as recovered as soon as the medical condition has returned to 
baseline status. 
** In case of a fatal event, the event term should not be “death” but the underlying event 
which led to death (death = outcome). If there is more than one AE in a fatal case, only the 
AE leading to death will be attributed with the outcome “fatal”. All other AEs ongoing at the 
time of death will be attributed with the outcome “not recovered/not resolved”. A copy of an 
autopsy report should be submitted if available. 
Assessment of causality 
The investigator is obligated to assess the relationship between trial treatment/trial 
procedure and each occurrence of each AE/SAE. 
The investigator will use clinical judgment to determine the relationship. 

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Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial treatment administration 
will be considered and investigated. 
It is sufficient to document the causality in the source data and CRF as: 
• 
Related (= there is a reasonable possibility of a causal relationship) or 
• 
Not related (= there is no reasonable possibility of a causal relationship) 
Relationship to trial treatment 
• 
The relationship or association of an AE or SAE to a trial treatment will be made by 
the investigator after having evaluated all accessible data and, if necessary, he/she 
will re-evaluate the case as new information becomes available. 
• 
Events caused by the procedure of trial treatment administration should be 
differentiated from events caused by the trial treatment itself. Only events 
suspected to be caused by the IMPs itself should be documented as suspected. 
Relationship to trial procedures including trial treatments 
• 
In this trial, it cannot be excluded that during the course of the trial some 
procedures give rise to AEs which are related to the trial procedure and not to the 
trial treatment. Procedure-related AEs can occur on the site of injection of the trial 
treatment e.g., redness, swelling, hematoma, or itching or during or after trial-
specific procedure, e.g., discomfort after blood drawing. 
• 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is very 
important that the investigator always makes an assessment of causality for every 
event before the initial transmission of the SAE data to the sponsor. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
10.3.1.8 
SAE exemptions 
In general, SAEs are defined according to ICH Topic E2A (CPMP/ICH/377/95), EU 
Directive 2001/20/EC, and ENTR/CT-3 (see Section 10.3.1.4). 
In the present trial, some events are excluded from the SAE definition. The following 
events do not need to be reported as SAEs: 
• 
AEs and SAEs occurring after trial subject discharge from the trial must only be 
reported by the investigator to the sponsor if a relationship to trial treatment or trial 
procedure is suspected. 
• 
Planned hospitalizations required by the protocol will not be considered as 
reportable SAEs. 

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10.3.1.9 
Documentation of particular situations 
AEs that are secondary to other events: 
In general, AEs that are secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events. A medically significant secondary AE that is separated in time 
from the initiating event should be documented as an independent AE in source data and 
CRF. For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy 
adult, only vomiting should be documented as AE. 
• 
If vomiting results in severe dehydration, both events should be documented as 
AEs separately. 
Abnormal clinical laboratory results and vital signs values: 
Not every laboratory or vital signs abnormality needs to be documented as AE. For 
clinically significant laboratory/vital signs abnormalities the following definitions and 
documentation rules apply: 
• 
If a laboratory/vital signs abnormality is a sign of a disease or syndrome, the 
laboratory/vital signs abnormality is clinically significant and only the diagnosis of 
the causing disease or syndrome needs to be documented as AE. 
• 
If a clinical laboratory/vital signs abnormality results in specific symptoms but no 
diagnosis of a disease or syndrome can be made, the laboratory/vital signs 
abnormality is clinically significant and only the symptoms need to be documented 
as AEs. 
• 
If a clinical laboratory/vital signs abnormality is not a sign of a disease or syndrome 
and does not result in specific symptoms but leads to a change in trial treatment or 
in a medical intervention, the laboratory/vital signs abnormality is clinically 
significant and must be documented as AE. 
• 
If a clinical laboratory/vital signs abnormality is not considered clinically significant 
by the investigator, then an AE does not need to be documented. 
AEs associated with an overdose or error in drug administration: 
• 
An overdose or incorrect administration of a drug is not itself an AE, but it may 
result in an AE. For a definition of an overdose, see Section 8.4. 
• 
All AEs associated with an overdose or incorrect administration should be 
documented as AE in source data and CRF and reported as SAE if applicable. 
AEs of proven COVID-19 disease: 
Any case of proven COVID-19 disease occurring until the last FU visit should be reported 
as an SAE/AE. 

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10.3.1.10 
Reporting of SAEs and AESIs 
All SAEs and AESI (even if the AESI is non-serious) which occur in a trial subject during 
the observation period, whether considered to be associated with trial medication or not, 
must be reported by the investigator to the sponsor within 24 h following knowledge of the 
event. 
All SAEs occurring after the end of the observation period only have to be reported to the 
sponsor if the investigator suspects a relationship to trial medication or the trial procedure. 
SAE and AESI reporting to sponsor 
For the period of observation, see Section 8.3.1. 
For any SAE or AESI (even if the AESI is non-serious), the investigator needs to complete 
the applicable paper Report Form which must be sent to the sponsor via one of the 
following reporting methods: 
• 
Safety Report Fax No.:   
 
• 
Safety Report Email Address:  
 
Information for final description and evaluation of a case report may not be available within 
the required time frames for reporting. Nevertheless, for regulatory purposes, initial reports 
should be submitted if the following minimal information is available: 
• 
An identifiable trial subject (trial subject number) 
• 
A suspected medicinal product 
• 
An identifiable reporting source (investigator/trial site identification) 
• 
An event or outcome that can be identified as serious 
All SAE/AESI follow-up information should be sent to the sponsor (indicating that this is a 
“follow-up” report using the SAE Form or the Additional Information and Follow-Up Form) 
without delay as described above and accompanied by appropriate anonymous supporting 
documentation (e.g., discharge letters, medical reports or death certificates), until a final 
outcome and date are available. All confidential information (name, address, full day of 
birth) needs to be blackened before sending. In addition to a medical record, the 
investigator should complete an Additional Information and Follow-Up Form, which 
contains the SAE term and trial subject number. 
A copy of the submitted SAE/AESI report must be retained on file by the investigator. If 
explicitly required according to national legislation, the investigator must submit copies of 
the SAEs to the IEC or authority and retain documentation of these submissions in the 
ISF. 
In case an investigator or any other trial team member has questions on safety reporting 
the sponsor may be contacted via: Email: 
 
For medical questions, the sponsor’s Medical Monitor for this trial should be contacted. 
CCI
CCI
CCI

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10.4 
Contraceptive guidance and collection of pregnancy 
information 
10.4.1 Definitions 
Women of childbearing potential 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of trial treatment, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP: 
• 
Premenarchal 
• 
Premenopausal female with one of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
For trial subjects with permanent infertility due to an alternate medical cause other than the 
above (e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining trial entry. 
Note: Documentation can come from the site personnel review of the trial subject’s 
medical records, medical examination, or medical history interview. 
Post-menopausal female 
A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
A high FSH level in the post-menopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal replacement 
therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required. 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the trial. Otherwise, they must discontinue HRT to allow confirmation of 
post-menopausal status before trial enrollment. 
Male trial subjects 
Male trial subjects with bilateral tubal occlusion, previous successful vasectomy or those 
who are truly abstinent or exclusively homosexual are deemed as being “not of 
reproductive potential”. 

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10.4.2 Contraception guidance 
Trial subjects must meet the “Reproductive status” inclusion criteria, including 
contraception requirements, as listed in Section 5.1. 
The investigator or delegate should advise the subject how to achieve highly effective 
contraception. The following birth control methods may be considered as highly effective: 
• 
Intrauterine device. * 
• 
Intrauterine hormone-releasing system. * 
• 
Combined estrogen and progestogen-based contraception: established use of oral, 
intravaginal, or transdermal hormonal methods of contraception. 
• 
Progesterone-based contraception: established use of oral, injected, or implanted 
hormonal methods of contraception. * 
• 
Sexual abstinence. ** 
* Contraception methods that in the context of this guidance are considered to have low 
user dependency. 
** In the context of this guidance sexual abstinence is considered a highly effective method 
only if defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the trial treatments. The reliability of sexual abstinence needs to be 
assessed in relation to its maintenance until Visit 5 (Day 50) and the preferred and usual 
lifestyle of the subject. 
10.4.3 Collection of pregnancy information 
Pregnancy information will only be collected after obtaining written informed consent from 
the pregnant trial subject/trial subject’s pregnant partner. 
The initial and follow-up information must be documented on the paper-based Pregnancy 
Reporting Form and submitted to the sponsor within 24 h of learning of a trial subject’s 
pregnancy/partner’s pregnancy. The completed form needs to be sent to the Safety Report 
Fax number or Email given in Section 10.3.1.10. Completed pregnancy forms must be 
signed by an investigator before faxing/mailing them to the sponsor. Blank reporting forms 
are provided to the investigator during the site initiation visit and are filed in the ISF. 
The investigator will collect follow-up information on the trial subject/trial subject’s partner 
and the neonate and the information will be forwarded to the sponsor. Pregnancy follow-up 
should describe the outcome of the pregnancy, including any voluntary or spontaneous 
termination, details of the birth, the presence or absence of any congenital abnormalities, 
birth defects, maternal or newborn complications and their presumed relation to the IMP. 
Generally, the follow-up will be of a duration determined in consultation with the 
pediatrician. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE. 
A spontaneous abortion is always considered to be an SAE and will be reported as such. 
Any post-trial pregnancy related SAE considered reasonably related to the trial 

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intervention by the investigator will be reported to the sponsor. While the investigator is not 
obligated to actively seek this information in former trial subjects, he or she may learn of 
an SAE through spontaneous reporting. 
10.4.4 Sperm donation 
Trial subjects must comply with the “Reproductive status” inclusion criteria prohibiting 
sperm donation listed in Section 5.1. 
10.5 
Genetics 
Not applicable. 
10.6 
Liver safety: Suggested actions and follow-up assessments 
Not applicable. 
10.7 
Investigators and trial administrative structure 
10.7.1 Investigators and trial site personnel 
There must be an investigator at each trial site. 
If the trial is conducted by a team of individuals at the trial site, the investigator leading and 
responsible for the team is called the principal investigator. 
All persons assigned responsibility as principal investigator must sign a declaration of their 
responsibilities and their agreement to this protocol before any trial-related procedure is 
performed. 
Curriculum vitae and/or other relevant documents confirming the current qualification of 
the investigators must be provided to the sponsor. This should include any previous 
training in the principles of GCP, experience obtained from work with clinical trials, and 
experience with trial subject care. 
Documentation of all involved investigators must be maintained according to GCP and 
applicable regulatory requirements. 
10.7.2 Trial site personnel assigned trial-related duties 
The principal investigator or deputy may define appropriately qualified personnel at a trial 
site to perform significant trial-related procedures and/or to make trial-related decisions 
under his/her supervision. In this case, the principal investigator must maintain a signed 
list of the persons to whom they delegate significant trial-related duties/responsibilities; the 
delegated trial-related duties/responsibilities must be specified in the list. 
When personnel or responsibility changes are made, the principal investigator or deputy 
must ensure that the relevant documentation is updated before any trial-related activities 
are performed. 

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10.10.4 
Investigator’s Site File and the Trial Master File 
The principal investigator or deputy is responsible for the filing of all essential documents 
in an ISF. The sponsor or a delegated CRO is responsible for the timely filing of all 
essential documents in the Trial Master File. As applicable, these files must be available at 
monitoring visits and during audits or regulatory inspections. 
After trial completion, the principal investigator or deputy must ensure that all source data 
and documentation related to the trial is recorded, handled, and stored in a way that allows 
its accurate reporting, interpretation, and verification. The principal investigator or deputy 
must take measures to prevent accidental or premature destruction of these documents. 
The principal investigator or deputy must keep the ISF, the source data/documentation 
arising from the trial according to the prescribed record retention period in the country 
and/or according to the hospital policy, but at least until informed by the sponsor that the 
trial-related records are no longer required. 
10.11 
Other data 
10.11.1 
Demographic data 
At screening, the following demographic data will be recorded for all trial subjects: 
• 
Age (in years/months) 
• 
Gender (male/female) 
• 
Ethnic group 
10.11.2 
Medical history 
Medical history information will be recorded for at the times given in the SoA (Section 1.3). 
11 
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