A Multi-site, Phase I/II, 2-Part, Dose-Escalation Trial Investigating the Safety and Immunogenicity of Four Prophylactic SARS-CoV-2 RNA Vaccines Against COVID-19 Using Different Dosing Regimens in Healthy and Immunocompromised Adults
Phase: PHASE1
Conditions: Infections, Respiratory, Virus Diseases, Infection Viral, Vaccine Adverse Reaction, RNA Virus Infections, Protection Against COVID-19 and Infections With SARS CoV 2
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  
INCLUDING AMENDMENTS NOS. 01 TO 09 
BNT162-01 
 
Version: 
13.0 
Date: 
12 JAN 2022 
Sponsor: 
BioNTech SE 
 
 
 
Trial title: 
A multi-site, Phase I/II, 2-part, dose escalation trial investigating the safety and 
immunogenicity of four prophylactic SARS-CoV-2 RNA vaccines against 
COVID-19 using different dosing regimens in healthy and 
immunocompromised adults 
Brief title: 
A multi-site Phase I/II trial investigating the safety and effects of four BNT162 
vaccines against COVID-19 in healthy and immunocompromised adults 
Trial phase: 
Phase I/II 
Indication: 
Protection against COVID-19 
Product: 
BNT162: SARS-CoV-2 - RNA lipid nanoparticle (RNA-LNP) vaccines utilizing 
different RNA formats, i.e., BNT162a1, BNT162b1, BNT162b2 and BNT162c2. 
Coordinating and 
Principal investigator:  
Dr. Dr. med. Armin Schultz, CRS Clinical Research Services 
Mannheim GmbH, Germany (tel.: +49 621 15045
) 
Trial sites: 
Multiple sites in Germany. For further details of the study sites and site 
personnel, see the Trial Master File (TMF). 
Contract research 
organization (CRO): 
CRS Clinical Research Services Mannheim GmbH, Germany 
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.: 2020-001038-36; ClinicalTrials.gov: NCT04380701; WHO UTN: 
U1111-1249-4220 
Medical Monitor: 
Contact information will be provided separately 
 
See the next page for a history of all sponsor-approved document versions and 
Section 10.10 for the rationale for all approved versions. 

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Document history 
Date 
Version number 
Valid for  
First approved version 
09 Apr 2020 
2.0 
Germany 
Amendment No. 1 
17 Apr 2020 
3.0 
Germany 
Amendment No. 2 
13 May 2020 
4.0 
Germany 
Amendment No. 3 
26 May 2020 
5.0 
Germany 
Amendment No. 4 
09 Jun 2020 
6.0 
Germany 
Amendment No. 4 
26 Jun 2020 
7.0 
Germany 
Amendment No. 5 
21 Jul 2020 
8.0 
Germany 
Amendment No. 6 
05 OCT 2020 
9.0 
Germany 
Amendment No. 6 
28 OCT 2020 
10.0 
Germany 
Amendment No. 7 
04 DEC 2020 
11.0 
Germany 
Amendment No. 8 
01 MAR 2021 
12.0 
Germany 
Amendment No. 9 
12 JAN 2022 
13.0 
Germany 

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Dose ranging cohorts: 
Trial subjects with the first-in-human (FIH) immunization will be immunized using a sentinel 
dosing/subject staggering (EMA 2017 guidance “Strategies to Identify and Mitigate Risks 
for First-in-Human and Early Clinical Trials with Investigational Medicinal Products”). The 
FIH starting dose and the planned escalation/de-escalation doses are given in Table 1. 
Dose escalation rules have been defined in this protocol to guide dose escalation. 
For all cohorts, if the investigator considers necessary, the planned observation periods 
before proceeding to dose further subjects in the same group may be prolonged by 
24 hours (h). 
Dose de-escalation in the case of possible vaccine-related toxicities will be guided by the 
Safety Review Committee (SRC), as required. 
In Cohort 1, the sentinel dosing/subject staggering process will be as follows: 
• One sentinel subject will be dosed on one day. 
• If the dosing in this subject was considered to be safe and well tolerated by the 
investigator after 24±2 h observation on site, a 5 further subjects will be dosed (with 
intervals of at least 1 h between subjects). 
• If the dosing in these 5 subjects was considered to be safe and well tolerated by the 
investigator based on 48 h data (24±2 h observation on site and phone interview for 
assessment 48±2 h after immunization; in addition to the available 48±2 h data from 
the sentinel subject): 
o The remaining 6 subjects in the group will be dosed (with intervals of at least 
30 minutes [min] between subjects). 
o If approved by the SRC, the next planned escalation dose (see Table 1) will 
be initiated. The data assessed by the SRC comprises 48 h data for 
6 subjects including observation on site, short summary of phone interview 
(including statement about diary reports), vital signs, investigator reported 
local and systemic reactions, treatment-emergent adverse events (TEAEs), 
solicited local & systemic reactions, blood/clinical laboratory data, and brief 
physical examination outcome. 
o If approved by the SRC, the planned de-escalation dose in Cohort 3 will be 
initiated. 
For any subsequent dose escalation cohorts (to doses higher than the maximum already 
tested for a vaccine candidate), the sentinel/subject staggering process will be as follows: 
• Two sentinel subjects will be dosed on one day (with intervals of at least 30 min 
between subjects). 
• If the dosing in these subjects was considered to be safe and well tolerated by the 
investigator after 24±2 h observation on site, a 4 further subjects will be dosed (with 
intervals of at least 30 min between subjects). 
• If the dosing in these 4 subjects was considered to be safe and well tolerated by the 
investigator based on 48 h data (24±2 h observation on site and phone interview for 

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assessment 48±2 h after immunization; in addition to the available 48 h data from 
the sentinel subjects): 
o The remaining 6 subjects in the group will be dosed (with intervals of at least 
30 min between subjects). 
o If approved by the SRC, the next planned escalation dose (see Table 1) will be 
initiated. The data assessed by the SRC comprises 48 h data for 6 subjects 
including observation on site, short summary of phone interview (including 
statement about diary reports), vital signs, investigator reported local and 
systemic reactions, TEAEs, solicited local & systemic reactions, blood/clinical 
laboratory data, and brief physical examination outcome. 
The maximum allowed dose for each vaccine candidate is defined in Table 1. 
For the planned dose de-escalation cohorts, 12 subjects may be dosed on one day (with 
intervals of at least 30 min between subjects). The doses in these cohorts in younger 
adults must be lower than doses that have shown acceptable tolerability in younger adults 
(based on the data from 12 subjects up until 48 h after the first dose). The same dose will 
not be administered twice, i.e., in two cohorts. 
For BNT162b1 and BNT162b2, administration of the planned 10 µg dose in older subjects 
(Cohort 8) may start once at least a 30 µg dose has shown acceptable tolerability in 
younger adults (based on the data from 12 subjects up until 48 h after the boost dose). 
The dose in Cohort 8 must also be confirmed by the SRC. In Cohort 8, 12 subjects will be 
dosed using a sentinel dosing/subject staggering (2-4-6) process with intervals of at least 
1 h between the first 6 subjects and then at least 30 min intervals for the remaining 
6 subjects. 
For BNT162b1 and BNT162b2, administration of the planned dose escalation cohorts in 
older adults (Cohorts 9 and 10), 12 subjects will be dosed using a sentinel dosing/subject 
staggering (2-4-6) process with intervals of at least 30 min between subjects. The doses 
planned in these cohorts will only be administered if the dose is confirmed by the SRC. 
The doses planned for Cohorts 8 to 10 are defined in Table 2. 
For the unplanned dose de-escalation cohorts, i.e., where the SRC requests the use of a 
reduced dose for safety reasons, 12 subjects may be dosed on one day with intervals of at 
least 30 min between subjects (as for planned de-escalation cohorts). 
Note: BNT162b1 and BNT162b2 are nucleoside modified RNAs, while BNT162a1 and 
BNT162c2 are both non-modified uridine containing RNAs. RNA modification is known to 
impact the extent of innate immune activation at a given dose level, and thus potentially 
the extent of reactogenicity. Therefore, tolerability data obtained with one of the vaccine 
variants of each of these pairs may be potentially informative for the respective other one 
and should be taken in consideration by the SRC for recommendations of lower or interim 
doses. 
In the case that an individual experiences dose limiting toxicities or that the frequency or 
pattern of adverse events (AEs) within a sub-cohort gives cause for concern, the 

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• Cohort 13: Population expansion cohort (including safety and long term immune 
response) with 30 immunocompromised adults who will receive of two 30 µg 
BNT162b2 doses given approximately 21 d apart (P/B regimen). 
For the scientific rationale for the expansion cohorts, see Section 4.2. 
All trial site visits for subjects in the expansion cohorts will be conducted on an outpatient 
basis, with the clinical judgment of the investigator determining whether a period of 
observation beyond that required for completion of study procedures is required, on a case 
by case basis. Standard measures to avoid cross-contamination of immunocompromised 
individuals with high risk pathogens should be followed for 24 months after the primary 
immunization. 
The European Medicines Agency (EMA) approval of a third dose of Comirnaty® has 
impacted the planned 2-year follow-up for Cohorts 11 to 13, with the subjects in this trial 
having the option to receive non-trial SARS-CoV-2 vaccinations (e.g., an authorized 
Comirnaty® vaccine within another BNT trial or within the government vaccination 
program). 
Biomarker (in-depth B cell immunity to SARS-CoV-2) Cohort 14: 
Protocol amendment 8.0 implements an additional cohort (Cohort 14) comprising an 
additional 20 healthy subjects aged from 18 to 85 years receiving BNT162b2 only. Two 
30 µg BNT162b2 doses will be given approximately 21 d apart (P/B regimen). 
Cohort 14 is intended to provide for additional characterization of B cell immune responses 
induced by BNT162b2. The planned dose of BNT162b2, two 30 µg BNT162b2 doses 
given 21 d apart, is the same regimen that has already been tested in the dose escalation 
phase of this trial and in more than 25,000 trial subjects (status 20 JAN 2021) in the 
ongoing global Phase I/II/III trial BNT162-02/C4591001 (NCT04368728). 
For the scientific rationale for Cohort 14, see Section 4.2. 
Part B 
Due to changes in the overall clinical development plan, Part B will no longer be 
conducted. 
 

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Key inclusion criteria 
Volunteers are only eligible to be enrolled in the trial if they meet the following criteria: 
• For younger adult cohorts, volunteers must be aged 18 to 55 years, have a BMI 
over 19 kg/m2 and under 30 kg/m2, and weigh at least 50 kg at Visit 0. 
OR  
For older adult cohorts, volunteers must be aged 56 to 85 years, have a BMI over 
19 kg/m2 and under 30 kg/m2, and weigh at least 50 kg at Visit 0. 
OR  
For the immunocompromised adult cohort (Cohort 13), volunteers must be aged 18 
to 85 years, have a BMI over 19 kg/m2 and under 30 kg/m2, and weigh at least 
50 kg at Visit 0. 
• They must be healthy, in the clinical judgment of the investigator, based on medical 
history, physical examination, 12-lead electrocardiogram (ECG), vital signs 
(systolic/diastolic blood pressure, pulse rate, body temperature, respiratory rate), 
and clinical laboratory tests (blood chemistry, hematology, and urine chemistry) at 
Visit 0. 
Note: Healthy volunteers with pre-existing stable disease, defined as disease not 
requiring significant change in therapy or hospitalization for worsening disease 
during the 6 weeks (wks) before enrollment, can be included. 
OR  
For the immunocompromised cohort (Cohort 13); volunteers who have previously 
received solid organ transplant, or peripheral blood stem cell transplantation 
≥6 months after transplantation, or individuals with human immunodeficiency virus 
(HIV) infection with a CD4+ T-cell count of ≥200 x 106/L at Visit 0. Individuals with 
lower T-cell counts will be excluded from the trial on the basis that this represents a 
significant medical complication. In the clinical judgment of the investigator, 
volunteers must be immunocompromised but otherwise healthy. After consultation 
with the Medical Monitor, this may include individuals receiving immunosuppressant 
therapy due to another confounding disease at least 2 wks prior to enrollment 
and/or at least 6 wks following immunization with BNT162b2, and/or individuals with 
immunosuppressive treatment of an autoimmune disease if the disease is stable. 
• Women of childbearing potential (WOCBP) must have a negative beta-human 
chorionic gonadotropin urine test at Visit 0 and Visit 1. Women that are 
postmenopausal or permanently sterilized will be considered as not having 
reproductive potential. 
Key exclusion criteria 
Volunteers are excluded from the trial if they present any of the following criteria: 
• Have had any acute illness, as determined by the investigator, with or without fever, 
within 72 h prior to any immunization. An acute illness which is nearly resolved with 
only minor residual symptoms remaining is allowable if, in the opinion of the 
investigator, the residual symptoms will not compromise their wellbeing if they 

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participate as trial subjects in the trial, or that could prevent, limit, or confound the 
protocol-specified assessments. 
• Have a known allergy, hypersensitivity, or intolerance to the planned investigational 
medicinal product (IMP) including any excipients of the IMP. 
• Had any medical condition or any major surgery (e.g., requiring general anesthesia) 
within the past 5 years which, in the opinion of the investigator, could compromise 
their wellbeing if they participate as trial subjects in the trial, or that could prevent, 
limit, or confound the protocol-specified assessments. See the inclusion criteria for 
non-excluded medical conditions for Cohort 13. 
• Have any surgery planned during the trial, starting after Visit 0 and continuously 
until at least 90 d after receiving the last immunization. 
• Had any chronic use (more than 21 continuous days) of any systemic medications, 
including immunosuppressants or other immune-modifying drugs (except for 
Cohort 13) within the 6 months prior to Visit 0, unless in the opinion of the 
investigator the medication would not prevent, limit, or confound the protocol-
specified assessments or could compromise subject safety. 
Note: Healthy volunteers with pre-existing stable disease, defined as disease not 
requiring significant change in therapy or hospitalization for worsening disease 
during the 6 wks before enrollment, can be included. 
• Regular receipt of inhaled/nebulized corticosteroids (except for Cohort 13). 
• Had any vaccination within the 28 d prior to Visit 0. 
• Had administration of any immunoglobulins and/or any blood products within the 
3 months prior to Visit 0. 
• Had administration of another IMP including vaccines within 60 d or 5 half-lives 
(whichever is longer), prior to Visit 0. 
• Have a known history of active or ongoing hepatitis B or hepatitis C infection; or 
except for Cohort 13: HIV-1 or HIV-2 infection within the 30 d prior to Visit 0. 
• Have a positive PCR-based test for SARS-CoV-2 within the 30 d prior to Visit 1. 
• Previously participated in an investigational trial involving lipid nanoparticles. 
• Have a history (within the past 5 years) of substance abuse or known medical, 
psychological, or social conditions which, in the opinion of the investigator, could 
compromise their wellbeing if they participate as trial subjects in the trial, or that 
could prevent, limit, or confound the protocol-specified assessments. 
• Have a history of hypersensitivity or serious reactions to previous vaccinations. 
• Have a history of Guillain-Barré syndrome within 6 wks following a previous 
vaccination. 
• Have a history of narcolepsy. 

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• (Except for Cohort 13) Have a history of or suspected immunosuppressive 
condition, acquired or congenital, as determined by medical history and/or physical 
examination at Visit 0. 
• Have symptoms of the Coronavirus Disease 2019 (COVID-19), e.g., respiratory 
symptoms, fever, cough, shortness of breath and breathing difficulties. 
• Have had contact with persons diagnosed with COVID-19 or who tested positive for 
SARS-CoV-2 by any diagnostic test within the 30 d prior to Visit 1. 
• Are soldiers, volunteers in detention, CRO or sponsor staff or their family members. 
• For older volunteers and for Cohort 13 only: Have a condition known to put them at 
high risk for severe COVID-19, including those with any of the following risk factors: 
− 
Uncontrolled hypertension. 
− 
Diabetes mellitus (HbA1c >8.5% ≥3 months, according to the medical history 
reported by the subject). 
− 
Chronic obstructive pulmonary disease. 
− 
Asthma. 
− 
Chronic liver disease. 
− 
Known Stage 3 or worse chronic kidney disease (glomerular filtration rate 
[GFR] of <60 mL/min/1.73 m2); Except for post-renal transplant patients who 
should have (estimated) GFR ≥40 mL/min/1.73 m2. 
− 
Serious heart conditions, such as heart failure, coronary artery disease, or 
cardiomyopathies. 
− 
Sickle cell disease. 
− 
Cancer (except for Cohort 13). 
− 
Are immune compromised due to stem cell or organ-transplantation with 
significant medical complications such as acute or chronic graft rejection or 
graft versus host disease requiring intensive immunosuppressive treatment, 
transplant failure, or infectious complications or other conditions that would be 
considered a contraindication for vaccination. 
− 
Are immune compromised due to HIV infection with a CD4+ count of 
<200 x 106/L at screening (Visit 0) or significant medical complications such as 
opportunistic infections, malignant complications (e.g., lymphoma, Kaposi 
sarcoma), other organ manifestations consistent with advanced acquired 
immunodeficiency syndrome (AIDS) or other conditions that would be 
considered a contraindication for vaccination. 
− 
Resident in a long term facility. 
− 
Current vaping or smoking (occasional smoking is acceptable). 
− 
History of chronic smoking within the prior year. 

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Trial treatments (BNT162 vaccines) 
Name: 
BNT162 vaccines - Antiviral RNA vaccines for active immunization against COVID-19 
Type: 
RNA-LNP vaccines utilizing different BioNTech RNA formats, i.e., uRNA (product code 
BNT162a1), modRNA (two variants, product codes BNT162b1 and BNT162b2), 
saRNA (product code BNT162c2) 
Dosage levels: 
Part A cohorts: 
See Table 1, Table 2, Table 3, and Table 4. The planned dose per vaccine candidate 
will not exceed the pre-defined maximum dose (see Table 1 and Table 2). The planned 
dose per vaccine candidate will not exceed the listed pre-defined maximum doses. 
Dosage 
frequency: 
One injection or two injections 21 d apart. Injection volumes will be up to 1.5 mL. 
Administration 
route: 
Intramuscular (IM); upper arm, musculus deltoideus. For the P/B regimens the same 
arm may be used for both immunizations. The non-dominant arm is preferred. 
Statistics 
The final analysis will be performed once all subjects have completed the end of treatment 
(EoT as defined in Section 1.3). An analysis update will be performed once all subjects will 
have completed the last planned visit. No formal interim statistical analysis will be 
performed. However, preliminary analyses based on all data collected until a pre-defined 
data cut-off date (snapshot analyses) may be performed for each cohort once subjects 
within a cohort will have been followed up for at least 7 d following each dose. 
Data Monitoring Committee (DMC)/SRC 
A DMC is not planned. A SRC is planned. 

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1.2 
Schema (graphical representation of the trial) 
For a graphical depiction of the cohorts in Part A, see Figure 1. For logistical reasons, 
investigation of the different vaccines may not be able to start at the same time. Should 
this happen, the expected overall trial duration may be extended. 
Dose ranging cohort schema for BNT162a1, BNT162b1, BNT162b2, and BNT162c2 (P/B) c 
Cohorts 1 to 7 with younger adults 
 
 
Cohorts 8 to 10 with older adults 
 
 
a) 
The data assessed by the SRC for progressing comprises 48 h data for 6 subjects. 
b) 
Subjects will be dosed using a sentinel dosing/subject (2-4-6) staggering process unless the planned dose is the same or lower 
than previously found to show acceptable tolerability (in which case, all subjects may be dosed on one day). 
c) 
For the dose regimens, see Table 1 and Table 2. 

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Dose ranging cohort schema for BNT162c2 (SD) b 
 
a) 
The data assessed by the SRC for progressing comprises 48 h data for 6 subjects. 
b) 
For the dose regimens, see Table 1. 
 
Expansion cohorts for BNT162b2 - Cohorts 11 to 13 a 
 
a) 
For the dose regimens, see Table 3. 
 
Biomarker (B cell and plasma cell immunity) cohort for BNT162b2 - Cohort 14 a 
 
a) 
For the dose regimen, see Table 4. 
 
Figure 1: 
Graphical depiction of the dose-finding and expansion process in Part A 
FIH = first-in-human; h = hour(s); SRC = Safety Review Committee. 

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a) 
Brief (symptom-directed) physical examination; no height measurement. 
b) 
At 1, 3, and 6 h (±15 min) after immunization. 
c) 
Vital signs: systolic/diastolic blood pressure, pulse rate, respiratory rate, and body temperature; body weight only at Visit 0. 
d) 
Urine screening for drugs of abuse (amphetamines, benzodiazepines, barbiturates, cocaine, cannabinoids, opiates, methadone, methamphetamines, phencyclidine, tricyclic antidepressants). 
e) 
Dipstick urine analysis: glucose, bilirubin, ketone, specific gravity, blood, pH, protein, urobilinogen, nitrite, and leukocytes. Microscopic urinalysis: if warranted by dipstick results, urine sediment will 
be microscopically examined for the presence of red blood cells, white blood cells, casts, crystals, epithelial cells, and bacteria. 
f) 
Clinical laboratory tests: (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; (Hematology) hemoglobin, hematocrit, red blood cell count, white blood cell count and differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count. Only in women who are not WOCBP (to confirm postmenopausal status): follicle stimulating hormone at Visit 0. 
g) 
Viral screening for human immunodeficiency virus (HIV) 1 or 2, hepatitis B, hepatitis C. 
h) 
Flexibility for visit days: Visit 3 Day 8±1 d; Visit 4 Day 22±2 d; Visit 5 Day 29±3 d; Visit 6 Day 43±4 d; Visit 7 Day 50±4 d; Visit 8 Day 85±7 d; Visit 9 Day 184±9 d. 
i) 
Only for the first 6 subjects per group. Questioning on and documentation of AEs as well as systemic and local reactions, the latter in case of upcoming dose decision meetings. 
j) 
Only IMP-related AEs and any SAEs except proven COVID-19 cases which have to be reported regardless on severity and relatedness to the trial drug until the last scheduled FU Visit as descr bed 
in Section 10.3.1.9. 
k) 
Blood draw for anti-SARS-CoV-2 antibodies. 
l) 
For Cohorts 1 and 8, immunization with at least 1 h intervals between subjects for the first 6 subjects and then with of at least 30 min intervals for the remaining 6 subjects. For all other cohorts and 
for all boost immunization, the intervals between subjects will be at least 30 min. 
m) Oral swipe for SARS-CoV-2 testing either on Day -1 or at the Visit 1 on Day 1. 
n) 
The timing of the listed “research” blood draw days may be adapted within the 200 mL maximum volume if justified by the collected data. Leftover blood after completion of the immunogenicity 
assessments may be used for additional analyses as described in Section 8.7 (Genetics) and/or Section 8.8 (Biomarkers). 
o) 
For subjects who have given consent, one aliquot of the blood sample drawn for analysis of CMI may be used for HLA typing to allow additional analysis of T-cell receptor repertoire and/or 
phenotypic characterization of T cells specific to vaccine-encoded antigens. 
p) 
If HLA typing using the blood sample collected with Lithium Heparin is not conclusive, EDTA-blood will be drawn for HLA testing. 
q) 
Only cohorts starting prime dosing after approval of protocol amendment 06. 
r) 
When entering the follow-up phase, i.e., after completing the EoT Visit, subjects are allowed to participate in other clinical trials not investigating COVID-19 vaccines or treatments. 
s) 
Record any medications that trial subjects receive during the trial in the CRF starting after Visit 0 and until the respective EoT Visit; record any vaccination, including SARS-CoV-2 vaccination, that 
subjects receive after the EoT Visit until the last FU Visit in the CRF. 
 
Notes: 
If the boost dose is not administered or if trial subjects permanently discontinue from IMP administration, subjects will complete all assessments listed in the SoA. 
The additional Visit 5a added by protocol amendment 06 will only apply for subjects who give consent. 
 
AE = adverse event; CMI = cell-mediated immune testing; CRF = case report form; D or d = day; ECG = electrocardiogram; EDTA = ethylenediamine tetraacetic acid; EoT = end of treatment (Visit); 
FU = follow-up (visit); h = hour(s); HLA = human leukocyte antigen; Day 0 = one day before Day 1; IMP = investigational medicinal product; min = minute(s); 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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r) 
Record any medications that trial subjects receive during the trial in the CRF starting after Visit 0 and until the respective EoT Visit; record any vaccination, including SARS-CoV-2 vaccination, that 
subjects receive after the EoT Visit until the last FU Visit in the CRF. 
 
AE = adverse event; CMI = cell-mediated immune testing; CRF = case report form; d = day; ECG = electrocardiogram; EDTA = ethylenediamine tetraacetic acid; EoT = end of treatment (Visit); 
FU = follow-up (visit); h = hour(s); HLA = human leukocyte antigen; IMP = investigational medicinal product; min = minute(s); SAE = serious adverse event; SARS-CoV-2 = the virus leading to 
COVID-19; WOCBP = women of childbearing potential. 

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d) 
Urine screening for drugs of abuse (amphetamines, benzodiazepines, barbiturates, cocaine, cannabinoids, opiates, methadone, methamphetamines, phencyclidine, tricyclic antidepressants). 
e) 
Dipstick urine analysis: glucose, bilirubin, ketone, specific gravity, blood, pH, protein, urobilinogen, nitrite, and leukocytes. Microscopic urinalysis: if warranted by dipstick results, urine sediment will 
be microscopically examined for the presence of red blood cells, white blood cells, casts, crystals, epithelial cells, and bacteria. 
f) 
Clinical laboratory tests: (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; (Hematology) hemoglobin, hematocrit, red blood cell count, white blood cell count and differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count. Only in women who are not WOCBP (to confirm postmenopausal status): follicle stimulating hormone at Visit 0. 
g) 
Viral screening for human immunodeficiency virus (HIV) 1 or 2, hepatitis B, hepatitis C. 
h) 
Flexibility for visit days: Visit 3 Day 8±1 d; Visit 4 Day 22±2 d; Visit 5 Day 29±3 d; Visit 5a Day 36±3 d; Visit 6 Day 43±4 d; Visit 7 Day 50±4 d; Visit 8 Day 85±7 d; Visit 9 Day 184±9 d; Visit 10 
Day 365±14 d; Visit 11 Day 547±14 d; Visit 12 Day 730±14 d. 
i) 
Only for HIV-positive subjects (done locally). 
j) 
Visits 8 and 9, only IMP-related AEs and any SAEs. Visits 10, 11, and 12, only any SAEs except proven COVID-19 cases which have to be reported regardless on severity and relatedness to the 
trial drug until the last scheduled FU Visit as described in Section 10.3.1.9. For 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). 
k) 
Blood draw for anti-SARS-CoV-2 antibodies. 
l) 
For first immunization in Cohort 13, immunization with at least 30 min intervals between the primary immunizations and 30 min between the boost immunizations. For Cohorts 11 and 12, the interval 
between the trial subjects will be at least 15 min for the prime immunizations and at least 5 min for the boost immunizations. 
m) Oral swipe for SARS-CoV-2 testing either on Day -1 or at the Visit 1 on Day 1. 
n) 
The timing of the listed “research” blood draw days may be adapted (within the 200 mL maximum volume) if justified by the collected data. Leftover blood after completion of the immunogenicity 
assessments may be used for additional analyses as described in Section 8.7 (Genetics) and/or Section 8.8 (Biomarkers). For subjects who receive non-trial SARS-CoV-2 vaccinations, there will be 
no blood sampling for immunogenicity or cell-mediated immune testing in the FU Visits. 
o) 
For subjects who have given consent, one aliquot of the blood sample drawn for analysis of CMI may be used for HLA typing to allow additional analysis of T-cell receptor repertoire and/or 
phenotypic characterization of T cells specific to vaccine-encoded antigens. 
p) 
If HLA typing using the blood sample collected with Lithium Heparin is not conclusive, EDTA-blood will be drawn for HLA testing. 
q) 
When entering the follow-up phase, i.e., after completing the EoT Visit, subjects are allowed to participate in other clinical trials not investigating COVID-19 vaccines or treatments (including 
immunosuppressants) except COVID-19 vaccine trials with booster BNT162b2 vaccines (i.e., where they are allowed). 
r) 
Record any medications that trial subjects receive during the trial in the CRF starting after Visit 0 and until the respective EoT Visit; record any vaccination, including SARS-CoV-2 vaccination, that 
subjects receive after the EoT Visit until the last FU Visit in the CRF. 
s) 
Subjects who receive non-trial SARS-CoV-2 vaccinations will be discontinued. Information about these vaccinations may be received outside of a planned visit and can be collected remotely, e.g., 
by phone. 
 
If the boost dose is not administered or if trial subjects permanently discontinued from IMP administration, subjects will complete all assessments listed in the SoA. 
Updates introduced by amendment 07 only apply for new consenting subjects after approval of the amendment. 
 
AE = adverse event; CMI = cell-mediated immune testing; CRF = case report form; D or d = day; ECG = electrocardiogram; EDTA = ethylenediamine tetraacetic acid; EoT = end of treatment (Visit); 
FU = follow-up (visit); h = hour(s); HLA = human leukocyte antigen; Day 0 = one day before Day 1; IMP = investigational medicinal product; min = minute(s); 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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q) 
Record any medications that trial subjects receive during the trial in the CRF starting after Visit 0 and until the respective EoT Visit; record any vaccination, including SARS-CoV-2 vaccination, that 
subjects receive after the EoT Visit until the last FU Visit in the CRF. 
 
Note: If a second dose of SARS-CoV-2 vaccine is not administered or if trial subjects permanently discontinue from IMP administration, subjects will be asked to complete all assessments listed in the 
SoA. 
 
AE = adverse event; CMI = cell-mediated immune testing; CRF = case report form; D or d = day; EDTA = ethylenediamine tetraacetic acid; EoT = end of treatment (Visit); h = hour(s); FU = follow-up 
(visit); HLA = human leukocyte antigen; Day 0 = one day before Day 1; IMP = investigational medicinal product; min = minute(s); 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 
3 
1.1 
Trial synopsis 
3 
1.2 
Schema (graphical representation of the trial) 
19 
1.3 
Schedule of activities 
21 
TABLE OF CONTENTS 
33 
LIST OF TABLES 
37 
LIST OF FIGURES 
37 
TRIAL-SPECIFIC ABBREVIATIONS/TERMS 
38 
2 
INTRODUCTION 
40 
2.1 
Background 
40 
2.1.1 
Overview of the disease 
40 
2.1.2 
Introduction to BioNTech RNA-based vaccines 
40 
2.2 
Trial rationale 
41 
2.3 
Benefit/risk assessment 
41 
2.3.1 
Risk assessment 
42 
2.3.2 
Benefit assessment 
46 
2.3.3 
Overall benefit/risk conclusion 
46 
3 
OBJECTIVES AND ENDPOINTS 
47 
4 
TRIAL DESIGN 
50 
4.1 
Overall design 
50 
4.1.1 
Adaptive trial design elements 
54 
4.1.2 
Planned number of trial subjects 
54 
4.2 
Scientific rationale for the trial design 
54 
4.3 
Justification for dose 
56 
4.4 
End of treatment (EoT) and end of trial definition 
57 
5 
TRIAL POPULATION 
58 
5.1 
Inclusion criteria 
58 
5.1.1 
Inclusion criteria Part A 
58 
5.2 
Exclusion criteria 
59 
5.2.1 
Exclusion criteria Part A 
59 
5.3 
Lifestyle considerations 
62 
5.4 
Screen failures 
63 
6 
TRIAL TREATMENTS 
63 
6.1 
IMP administered 
63 
6.2 
Preparation/handling/storage/accountability 
63 
6.3 
Measures to minimize bias: randomization and blinding 
64 

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6.4 
Trial treatment compliance 
64 
6.5 
Concomitant therapy 
64 
6.5.1 
Premedication 
65 
6.5.2 
Rescue medication 
65 
6.6 
Dose modifications 
65 
6.6.1 
Dose limiting toxicity 
65 
6.6.2 
Dose modification guidance/rules 
66 
6.6.3 
Mitigation plans for specific AEs 
67 
6.6.4 
Safety stopping criteria 
67 
6.7 
Treatment after the end of the trial 
67 
7 
DISCONTINUATION OF TRIAL TREATMENT AND TRIAL SUBJECT 
DISCONTINUATION/WITHDRAWAL 
68 
7.1 
Discontinuation of trial treatment 
68 
7.1.1 
Temporary discontinuation 
68 
7.1.2 
Rechallenge 
68 
7.2 
Trial subject discontinuation/withdrawal from the trial 
68 
7.3 
Lost to follow-up 
69 
7.4 
Replacement of permanently discontinued trial subjects 
69 
8 
TRIAL ASSESSMENTS AND PROCEDURES 
69 
8.1 
Efficacy assessments 
70 
8.2 
Safety assessments 
70 
8.2.1 
Physical examinations 
70 
8.2.2 
Vital signs 
70 
8.2.3 
Electrocardiograms 
71 
8.2.4 
Clinical laboratory tests 
71 
8.2.5 
Drugs of abuse screening 
71 
8.2.6 
Testing for alcohol use 
71 
8.2.7 
Viral screening (for blood-borne viruses) 
71 
8.2.8 
Subject diaries 
72 
8.2.9 
Assessment of local reactions 
72 
8.2.10 
SARS-CoV-2 testing 
72 
8.2.11 
Subject hotline 
73 
8.2.12 
Subject wellbeing questioning 
73 
8.2.13 
Assessment of systemic reactions 
73 
8.3 
Adverse events and serious adverse events 
74 
8.3.1 
Time period and frequency for collecting AE and SAE information 
74 
8.3.2 
Method of detecting AEs and SAEs 
74 
8.3.3 
Follow-up of AEs and SAEs 
74 

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8.3.4 
Regulatory reporting requirements for SAEs 
75 
8.3.5 
Pregnancy 
75 
8.3.6 
Death events 
76 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs 
or SAEs 
76 
8.3.8 
Adverse events of special interest 
76 
8.4 
Treatment of overdose 
76 
8.5 
Pharmacokinetics 
77 
8.6 
Pharmacodynamics 
77 
8.7 
Genetics 
77 
8.8 
Biomarkers (CMI responses, explorative biomarker, immunogenicity research 
purposes) 
77 
8.9 
Biomarkers (B cells) 
78 
8.10 
Immunogenicity assessments 
79 
8.11 
Blood collection 
80 
8.12 
Saliva and stool collection 
80 
9 
STATISTICAL CONSIDERATIONS 
81 
9.1 
Statistical hypotheses 
81 
9.2 
Sample size determination 
81 
9.3 
Analysis sets 
81 
9.4 
Statistical analyses 
81 
9.4.1 
General considerations 
82 
9.4.2 
Primary endpoints 
82 
9.4.3 
Secondary endpoints 
83 
9.4.4 
Exploratory endpoints 
83 
9.4.5 
Other safety analyses 
83 
9.4.6 
Other analyses 
84 
9.5 
Interim analyses 
84 
9.6 
Data Monitoring Committee 
85 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
 
 
85 
10.1 
Regulatory, ethical, and trial oversight considerations 
85 
10.1.1 
Regulatory and ethical considerations 
85 
10.1.2 
Financial disclosure 
86 
10.1.3 
Informed consent process 
86 
10.1.4 
Data protection 
86 
10.1.5 
Committees - SRC 
87 
10.1.6 
Dissemination of clinical trial data 
87 
10.1.7 
Data quality assurance 
87 

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10.1.8 
Source documents 
88 
10.1.9 
Trial and site start and closure 
88 
10.1.10 
Publication policy 
89 
10.1.11 
Protocol preparation and approval 
89 
10.2 
Clinical laboratory tests 
89 
10.3 
Adverse events: Definitions and procedures for recording, evaluating, follow-up, 
and reporting 
90 
10.3.1 
Definition of AE and TEAE 
90 
10.4 
Contraceptive guidance and collection of pregnancy information 
102 
10.4.1 
Definitions 
102 
10.4.2 
Contraception guidance 
102 
10.4.3 
Collection of pregnancy Information 
103 
10.4.4 
Sperm donation 
104 
10.5 
Genetics 
104 
10.6 
Liver safety: Suggested actions and follow-up assessments 
104 
10.7 
Investigators and trial administrative structure 
104 
10.7.1 
Investigators and trial site personnel 
104 
10.7.2 
Trial site personnel assigned trial-related duties 
104 
10.7.3 
Contract research organizations 
105 
10.7.4 
The sponsor and sponsor’s personnel 
105 
10.8 
Country-specific requirements 
105 
10.9 
Other standard abbreviations and definitions 
106 
10.10 
Protocol amendments and version updates 
107 
10.10.1 
Protocol amendment no. 01 
107 
10.10.2 
Protocol amendment no. 02 
107 
10.10.3 
Protocol amendment no. 03 
107 
10.10.4 
Protocol amendment no. 04 
108 
10.10.5 
Protocol amendment no. 05 
108 
10.10.6 
Protocol amendment no. 06 
108 
10.10.7 
Protocol amendment no. 06 (protocol version 10.0) 
110 
10.10.8 
Protocol amendment no. 07 (protocol version 11.0) 
110 
10.10.9 
Protocol amendment no. 08 (protocol version 12.0) 
110 
10.10.10 Protocol amendment no. 09 (protocol version 13.0) 
111 
10.11 
Data collection and management 
111 
10.11.1 
Case report forms 
111 
10.11.2 
Trial subject reported outcomes 
111 
10.11.3 
Data management 
111 
10.11.4 
Investigator’s Site File and the Trial Master File 
112 

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10.12 
Other data 
112 
10.12.1 
Demographic data 
112 
10.12.2 
Medical history 
112 
11 
REFERENCES 
112 
 
LIST OF TABLES 
Table 1: 
Dose ranging: vaccine dose regimens for younger adults aged 18 to 55 years in 
Part A (Cohorts 1 to 7) 
11 
Table 2: 
Dose ranging: vaccine dose regimens for older adults aged 56 to 85 years in 
Part A (Cohorts 8 to 10) 
12 
Table 3: 
Expansion cohorts for BNT162b2 (ages 18 to 85 years) in Part A (Cohorts 11 to 
13)  
13 
Table 4: 
Cohort 14 for BNT162b2 (ages 18 to 85 years) in Part A 
13 
Table 5: 
Overview of the total number of subjects for each vaccine in Part A 
14 
Table 6: 
Schedule of trial procedures and assessments – BNT162a1, BNT162b1, 
BNT162b2, and BNT162c2 when tested P/B (excluding Cohorts 11 to 14) 
21 
Table 7: 
Schedule of trial procedures and assessments – BNT162c2 (SD) 
24 
Table 8: 
Schedule of trial procedures and assessments – Cohorts 11 to 13 (Expansion 
cohorts only) 
27 
Table 9: 
Schedule of trial procedures and assessments – BNT162b2 and B cell immunity 
(Cohort 14) 
30 
Table 10: Probability to observe a particular TEAE at least once 
81 
Table 11: Local reaction grading scale 
99 
Table 12: Systemic reaction grading scale 
100 
Table 13: Fever grading scale 
100 
Table 14: Laboratory abnormality grading scale 
101 
 
LIST OF FIGURES 
Figure 1: Graphical depiction of the dose-finding and expansion process in Part A 
20 
 

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NOTES FOR THE READER 
When the term “must” is used, the action/item is always mandatory. Non-compliance with 
this instruction constitutes a protocol deviation. When the term “should” is used, the 
action/item is recommended but not mandatory. Non-compliance with this instruction does 
not constitute a protocol deviation. 
 

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2 
INTRODUCTION 
2.1 
Background 
2.1.1 
Overview of the disease 
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections and the 
caused disease Coronavirus Disease 2019 (COVID-19) are increasing every day and 
spreading globally, affecting more and more countries. 
On March 11th, 2020 the World Health Organization (WHO) characterized the COVID-19 
outbreak as pandemic. 
The WHO Situation Update Report dated April 15th, 2020 noted 1,914,916 confirmed 
cases with 123,010 deaths globally, including 977,596 confirmed cases with 84,607 deaths 
in the European region (WHO Situation Report Nr. 85). 
2.1.2 
Introduction to BioNTech RNA-based vaccines 
An LNP-formulated RNA-based vaccine would provide one of the most flexible, scalable 
and fastest approaches to provide protection against the emerging viruses like 
SARS-CoV-2 (Rauch et al. 2018; Sahin et al. 2014). 
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. Unlike live attenuated 
vaccines, RNA vaccines do not carry the risks associated with infection and may be given 
to people who cannot be administered live virus (such as pregnant women and 
immunocompromised persons). RNA-based vaccines are manufactured via a cell-free 
in vitro transcription process, which allows an easy and rapid production, and the prospect 
of producing high numbers of vaccination doses within a shorter time period than achieved 
with conventional vaccine approaches. This capability is pivotal to enable the most 
effective response in outbreak scenarios. 
The development of in vitro transcribed RNA as an active platform for the use in infectious 
disease vaccines is based on the extensive knowledge of the company in RNA 
technology, which has been gained over the last decade. The core innovation is based on 
in vivo delivery of a pharmacologically optimized, antigen-encoding RNA to induce robust 
neutralizing antibodies and a concomitant T-cell response to achieve protective 
immunization with minimal vaccine doses (Vogel et al. 2018; Moyo et al. 2018; 
Pardi et al. 2017). 
At BioNTech, there are three different RNA platforms under development, namely non-
modified uridine containing mRNA (uRNA, BNT162a), nucleoside modified mRNA 
(modRNA, BNT162b), and self-amplifying mRNA (saRNA, BNT162c). 
All three RNA platforms have been tested in more than a dozen non-clinical GLP safety 
studies and, for uRNA and modRNA, there is pre-existing clinical safety data (see the 
BNT162 investigator’s brochure [IB]). These data have been obtained primarily with RNAs 

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formulated with liposomes which are related, but not identical, to those to be used in this 
trial. 
The non-clinical toxicity data generated by BioNTech suggest a favorable safety profile for 
uRNA and modRNA, as well as saRNA formulated with different nanoparticles for various 
administration routes, including intravenous (IV) injection. The favorable safety profile after 
IV dosing is notable because it results in a higher systemic exposure than the planned IM 
dosing in this trial. Overall, the findings were mild and mostly related to the mode-of-action 
and the RNA-intrinsic stimulation of innate immune sensors. No unsuspected target 
organs of toxicity were identified. The non-clinical safety profile of uRNA and modRNA in 
rodents was predictive for clinical safety. For further details, see the BNT162 IB. 
The safety and toxicity of the lipid nanoparticle enveloped uRNA, modRNA, and saRNA 
vaccines encoding coronavirus antigens is currently being analyzed in a GLP-compliant 
repeated-dose toxicity study. 
A recently published clinical trial using an influenza vaccine based on modRNA 
encapsulated in LNPs highly related to those used in this trial and also administered IM 
reported good safety and well tolerability (Feldman et al. 2019). 
2.2 
Trial rationale 
SARS-CoV-2 infections and the caused disease COVID-19 are increasing every day and 
spreading globally, affecting more and more countries, and carrying a high risk of rapidly 
becoming pandemic (for more details, see Section 2.1.1). There are currently no vaccines 
or antiviral drugs to treat these infections or its caused disease COVID-19. Therefore, 
there is an unmet need for the rapid development of effective prophylactic vaccines. 
BioNTech has developed a technology platform of RNA-based vaccines which enables the 
rapid development of vaccines against emerging viral diseases (for more details, see 
Section 2.1.2). This technology platform is especially attractive because it has the ability to 
deliver high numbers of vaccine doses rapidly in a single production campaign. 
This trial investigates the potential safety and immunogenicity of four prophylactic BNT162 
vaccines against SARS-CoV-2, BNT162a1, BNT162b1, BNT162b2, and BNT162c2. The 
two variants of the BNT162b vaccines, BNT162b1 and BNT162b2, differ in the encoded 
antigen. 
Some of the prophylactic BNT162 vaccines against SARS-CoV-2 investigated in this trial 
are under investigation in other ongoing trials. For the design, status, and a summary of 
the available results of the ongoing clinical trials, see the BNT162 IB. 
2.3 
Benefit/risk assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected TEAEs for this trial are given in the BNT162 IB. 

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2.3.1 
Risk assessment 
The risks linked to the trial-specific procedures and connected mitigations are as follows: 
• The volume of blood drawn will be kept to a minimum and will remain less than that 
drawn when donating blood: 
o For subjects in Cohorts 1 to 10, up to approximately 592 mL blood will be drawn 
per subject over the complete trial, i.e., over approximately 223 d. 
o For subjects in Cohorts 11 to 13, up to approximately 1,025 mL blood will be 
drawn per subject over the complete trial, i.e., over approximately 760 d. 
o For subjects in Cohort 14, up to approximately 477 mL blood will be drawn per 
subject over the complete trial, i.e., over approximately 223 d. 
• All trial-specific procedures will be performed by qualified trial site personnel. 
• Immunization will be done by a physician. 
• Human experience with BNT162 vaccines was not available prior to this trial. 
However, clinical data was available for RNAs formulated with related but not 
identical liposomal compositions or non-formulated RNAs and can support risk 
assessment of the BNT162 vaccines. 
Based on such data, the risks linked to the immunization with the BNT162 vaccines are as 
follows: 
• Due to the IM route of administration, there is the risk of local reactions at the 
injection site, e.g., erythema, pruritus, pain, tenderness, swelling, sweating. 
• Due to their immune-modulatory effect, vaccines may cause systemic flu-like 
reactions such as temporary headache, fatigue, loss of appetite, myalgia, arthralgia, 
fever. Rarely, with certain prophylactic vaccines (e.g., as seen for vaccines using 
attenuated viruses) severe allergic reaction or a neurological side effects, such as a 
seizure, were seen. Although these rare side effects are a concern, the risk of a 
vaccine causing serious harm or death is considered to be extremely small, in 
particular for BNT162 vaccines, which are molecularly defined, highly purified and 
based on RNA, which naturally occurs and is metabolized in the human organism. 
• Due to the IM route the risk of systemic reactions is considered low. 
• As with other vaccines, and with single stranded RNA being an innate immune 
sensor-agonist, BNT162 vaccine administration may cause temporary headache, 
fatigue, or loss of appetite. Rarely, with certain prophylactic vaccines (e.g., as seen 
for vaccines using attenuated viruses) severe allergic reactions or neurological side 
effects, such as seizures, were seen. Although these rare side effects are a 
concern, the risk of a vaccine causing serious harm or death is considered to be 
extremely small, in particular for BNT162 vaccines, which are molecularly defined, 
highly purified, subunit vaccines. 
The available non-clinical data of BNT162a, BNT162b, and BNT162c suggest a favorable 
safety profile with events that are mild and mostly related to the mode-of-action and the 
RNA-intrinsic stimulation of innate immune sensors. 

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• Based on the available clinical and non-clinical data on the individual components 
(uRNA, modRNA, saRNA, the specific LNP formulation), that are combined within 
the BNT162 products, a favorable safety profile of BNT162 products is expected 
with mild and localized effects (see the BNT162 IB for details on these trials). 
To date, based on available clinical experience with BNT162 vaccines in human subjects: 
• Generally, good tolerability was observed. Overall, many of the reported TEAEs 
appear to be similar to reactogenicity events anticipated for IM-administered 
vaccines, typically with an onset within first 24 h post immunization. All events / 
reactogenicity symptoms resolved spontaneously, mostly within 24 h of onset, and 
were managed with simple measures (e.g., paracetamol). There were no serious 
adverse events (SAEs) and no unexpected toxicities. Most TEAEs were managed 
with simple measures and resolved spontaneously. 
• The adverse reactions (AEs for which there is a reason to conclude that the vaccine 
caused the events) identified for BNT162 vaccines at this time are: injection site 
pain, fever, fatigue, headache, chills, and muscle pain. 
• While the general risk of effects potentially associated with the innate immune 
activation and transient secretion of associated cytokines are defined above based 
on the described data, the dose response-relationship, and thus the tolerability for 
the BNT162 vaccine candidates will only be defined by the ongoing trials (for a 
summary of the ongoing trials, see the BNT162 IB). 
• The clinical experience after P/B dosing with BNT162b1 at 10, 20, and 30 µg and 
single doses of BNT162b2 at 10, 20, and 30 µg, in healthy elderly adults aged 65 to 
85 years is summarized in the BNT162 IB. 
• The local tolerability of BNT162b1 and BNT162b2 in elderly adults seemed 
comparable to that recorded in younger adults aged 18 to 55 years. Likewise, the 
pattern of systemic reactogenicity appeared similar between the 2 age groups, 
possibly with a lower overall incidence in the elderly adults in comparison to the 
younger adults at equal doses (for details, see the BNT162 IB). 
• Preliminary data in elderly adults, show lower but measurable antibody responses 
in older adults than in younger adults (for details, see the BNT162 IB). The 
investigation of higher dose range in older adults in this trial may therefore be 
required to support the Phase III program planned to support marketing approval. 
• When assessing the risk for dosing of older subjects with BNT162 vaccine 
candidates in this trial, the follow information is relevant: 
− 
Preliminary data in subjects treated in the ongoing BNT162 trials backed by 
non-human primate (rhesus macaque) immunogenicity data have shown that 
BNT162b1 in the tested dose range is immunogenic. 
− 
The risk that older adults may be under dosed with the vaccine doses chosen 
based on data for younger adults (as was observed for other vaccines). 

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− 
Preliminary data in elderly show a comparable to lower reactogenicity based on 
the observed local reactions and system events in similar doses. This 
observation may indicate a lower innate response in younger adults. 
− 
In this trial, the P/B BNT162b1 and BNT162b2 doses planned in older adults 
(10, 20, and 30 µg) are within the range already shown to show acceptable 
tolerability in younger adults and in elderly adults in this trial and/or BNT162-02 
trial (for details, see the BNT162 IB). This tolerability in elderly adults appears 
to be better than seen in younger adults at the same doses. 
− 
Although using doses already found to show acceptable tolerability in younger 
adults and an even better tolerability in elderly adults, this trial implements 
numerous safety measures (e.g., sentinel dosing/staggering of subjects, on site 
observation periods after each immunization, wellbeing questioning, frequent 
on site visits after immunization). 
− 
This trial includes inclusion/exclusion criteria to exclude potential risk factors 
relevant for all adults, but additional criteria have been included to further 
protect the safety of enrolled older adults. 
• The listed risks can be managed using routine symptom driven standard of care as 
described in Section 6.6.3. Treatment of these events is dependent on the 
discretion of the investigators. 
• Since this trial involves the first immunization of humans with the BNT162 vaccines, 
in the FIH cohorts and all dose escalation cohorts use a sentinel dosing/staggering 
of subjects (EMA 2017 guidance “Strategies to Identify and Mitigate Risks for First-
in-Human and Early Clinical Trials with Investigational Medicinal Products”). 
To further ensure trial subject safety during dose ranging cohorts, the trial protocol 
foresees that: 
• On site observation periods after each immunization (i.e., 24 h for the first 
6 subjects per group and 6 h for other subjects in the same group) that are much 
longer than used in recently completed FIH clinical trials investigating related RNA-
based vaccines. For example, the 2 Moderna trials investigating mRNA vaccines 
against avian H10N8 and H7N9 influenza viruses in healthy adults (Feldman et al. 
2019) that observed trial subjects on site for only 1 h after each immunization 
before discharge from the trial site. 
• More frequent on site visits after immunization (i.e., on Days 2 and 8) than used in 
recently completed FIH clinical trials investigating with related RNA-based vaccines, 
e.g., the 2 Moderna trials investigating mRNA vaccines against avian H10N8 and 
H7N9 influenza viruses in healthy adults (Feldman et al. 2019) that used on site 
visits on Day 8. 
• Subject wellbeing questioning by telephone at 48±2 h after each immunization 
(where applicable, after both the prime and boost immunizations) will be performed 
for the first 6 subjects per cohort. Additional subject wellbeing calls may be included 
at the discretion of the SRC. 

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• In the case that an individual experiences dose limiting toxicities or that the 
frequency or pattern of AEs within a sub-cohort gives cause for concern, the 
investigator may request an ad hoc review by the SRC before further doses of a 
given vaccine construct are administered. 
• If the investigator considers necessary, the planned observation periods before 
proceeding to dose further subjects in the same group may be prolonged by 24 h. 
• The SRC must assess the safety and tolerability data of the first 6 subjects before 
allowing progression to the next cohort, for each vaccine per cohort/dose level. 
• After each assessment, the SRC may request a prolongation of the observation 
periods to up to Day 7 for later cohorts. Experience in this ongoing trial and in the 
ongoing BNT162-02 trial, has confirmed the adequacy of the implemented 
observations periods. 
• The SRC may make recommendations on increasing observation periods and 
additional subject wellbeing calls may be included at the discretion of the SRC. 
• To ensure trial subject safety during the trial, their safety will be monitored from 
Visit 0 (screening) until approximately 6 months after the last immunization. 
For the expansion cohorts: 
• Due to the extensive experience and exposure already achieved with BNT162b2 at 
30 µg in the ongoing global Phase I/II/III trial (from which frequent, rolling safety 
data submissions to health authorities are being made) the measures implemented 
for dose ranging cohorts are deemed unnecessary for the expansion cohorts (by 
20 JAN 2021, more than 25,000 trial subjects have been dosed at least once with 
BNT162b2). 
• Immunocompromised individuals are considered at increased risk from infection 
with SARS-CoV-2 and of infections in general. Risk minimization measures already 
in place for the protection of all subjects in this trial are also considered sufficient to 
protect this increased risk group, who are generally regarded as ambulatory in 
nature. Care should however be taken to avoid unnecessary extension of on site 
time and site visits for these subjects, to minimize their risk of exposure to high risk 
pathogens. 
Vaccine-related enhanced disease has been reported in the literature from non-clinical 
studies investigating different vaccine formulations tested to prevent various coronavirus-
induced diseases. Such effects have not been documented so far for SARS-CoV-2. No 
data are currently available to exclude that BNT162 may cause enhanced disease in 
vaccinated subjects. 
The risks linked to the pandemic COVID-19 outbreak will be managed by requiring that the 
trial subjects: 
• Avoid contact with persons tested positive for SARS-CoV-2 antibodies or have an 
increased risk for infection during their participation in the trial. 

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• Practice social distancing and follow good practices to reduce their chances of 
being infected or spreading COVID-19 during their participation in the trial. 
• Complete health status checks which include symptom-directed physical 
examinations, vital signs assessments, and clinical laboratory tests at the planned 
visit days. 
• Use the Subject Hotline 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., enhanced respiratory disease or flu-
like symptoms, may trigger diagnostic measures at the discretion of the investigator. 
To minimize the risk to trial subjects in this trial, an SRC will regularly review and evaluate 
the safety and immunogenicity data. For details, see Section 10.1.5. 
2.3.2 
Benefit assessment 
After participating in this trial, depending on the immunization regimen followed, some trial 
subjects should be immune against SARS-CoV-2 infection. 
There is an urgent need for the development of new prophylactic vaccines given the threat 
posed by the increasing number of globally distributed outbreaks of SARS-CoV-2 infection. 
The BioNTech platform of RNA-based vaccines being tested in this trial is especially 
attractive because it has the ability to deliver high numbers of vaccine doses rapidly in a 
single production campaign. This platform has the added advantage of not employing live 
virus and could therefore potentially be used for immuno-compromised populations. 
By participating in this trial, the trial subjects will support the development of one or more 
prophylactic vaccines against SARS-CoV-2 infection. 
2.3.3 
Overall benefit/risk conclusion 
Overall, the sponsor considers the benefit/risk ratio to be acceptable for a trial of this type. 

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4 
TRIAL DESIGN 
4.1 
Overall design 
This trial has two parts. Part A and Part B. Due to changes in the overall clinical 
development plan, Part B will no longer be conducted. The objectives originally described 
for Part B have been implemented in the ongoing development via a pivotal Phase I/II/III 
trial BNT162-02/C4591001 (NCT04368728). 
Part A is for dose ranging of four different vaccines (BNT162a1, BNT162b1, BNT162b2, 
and BNT162c2) will be undertaken with dose escalation and de-escalation plus the 
evaluation of interim dose levels. It also includes dose ranging in older subjects. 
The vaccines BNT162a1, BNT162b1, BNT162b2, and BNT162c2 will be administered 
using a P/B regimen. The vaccine BNT162c2 will also be administered using a 
SD regimen. 
BNT162b2, for which the dose regimen has been determined in the dose ranging in Part A 
of this trial, has now entered efficacy evaluation in the ongoing development via a pivotal 
Phase I/II/III trial BNT162-02/C4591001 (NCT04368728). Therefore, for BNT162b2, 
amendment 06 of this trial introduced expansion cohorts designed to expand the existing 
safety profiling to a broader population and to enable detailed characterization of the 
adaptive immune responses, including determine factors that impact them. These cohorts 
will involve healthy and immunocompromised populations treated according to the 
selected dosing posology and exploring an alternative posology. 
The chosen trial design reflects discussion and advice from the PEI obtained in scientific 
advice meetings held in February, March, and June 2020 in response to a fast-changing 
situation. 
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. 
Part A 
The first part of the trial (Part A) will follow a dose escalation design. Discretionary dose 
de-escalation and refinement is also planned. Part A will consist of a screening/treatment 
phase and a follow-up phase. 
Dose ranging cohorts: 
Trial subjects with the FIH immunization will be immunized using a sentinel dosing/subject 
staggering (EMA 2017 guidance “Strategies to Identify and Mitigate Risks for First-in-
Human and Early Clinical Trials with Investigational Medicinal Products”). The FIH starting 
dose and the planned escalation/de-escalation doses are given in Table 1. Dose 
escalation rules have been defined in this protocol to guide dose escalation. 
For all cohorts, if the investigator considers necessary, the planned observation periods 
before proceeding to dose further subjects in the same group may be prolonged by 24 h. 
Dose de-escalation in the case of possible vaccine-related toxicities will be guided by the 
Safety Review Committee (SRC), as required. 

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In Cohort 1, the sentinel dosing/subject staggering process will be as follows: 
• One sentinel subject will be dosed on one day. 
• If the dosing in this subject was considered to be safe and well tolerated by the 
investigator after 24±2 h observation on site, a 5 further subjects will be dosed (with 
intervals of at least 1 h between subjects). 
• If the dosing in these 5 subjects was considered to be safe and well tolerated by the 
investigator based on 48 h data (24±2 h observation on site and phone interview for 
assessment 48±2 h after immunization; in addition to the available 48±2 h data from 
the sentinel subject): 
o The remaining 6 subjects in the group will be dosed (with intervals of at least 
30 min between subjects). 
o If approved by the SRC, the next planned escalation dose (see Table 1) will 
be initiated. The data assessed by the SRC comprises 48 h data for 
6 subjects including observation on site, short summary of phone interview 
(including statement about diary reports), vital signs, investigator reported 
local and systemic reactions, TEAEs, solicited local & systemic reactions, 
blood/clinical laboratory data, and brief physical examination outcome. 
o If approved by the SRC, the planned de-escalation dose in Cohort 3 will be 
initiated. 
For any subsequent dose escalation cohorts (to doses higher than the maximum already 
tested for a vaccine candidate), the sentinel/subject staggering process will be as follows: 
• Two sentinel subjects will be dosed on one day (with intervals of at least 30 min 
between subjects). 
• If the dosing in these subjects was considered to be safe and well tolerated by the 
investigator after 24±2 h observation on site, a 4 further subjects will be dosed (with 
intervals of at least 30 min between subjects). 
• If the dosing in these 4 subjects was considered to be safe and well tolerated by the 
investigator based on 48 h data (24±2 h observation on site and phone interview for 
assessment 48±2 h after immunization; in addition to the available 48 h data from 
the sentinel subjects): 
o The remaining 6 subjects in the group will be dosed (with intervals of at least 
30 min between subjects). 
o If approved by the SRC, the next planned escalation dose (see Table 1) will be 
initiated. The data assessed by the SRC comprises 48 h data for 6 subjects 
including observation on site, short summary of phone interview (including 
statement about diary reports), vital signs, investigator reported local and 
systemic reactions, TEAEs, solicited local & systemic reactions, blood/clinical 
laboratory data, and brief physical examination outcome. 
The maximum allowed dose for each vaccine candidate is defined in Table 1. 

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For the planned dose de-escalation cohorts, 12 subjects may be dosed on one day (with 
intervals of at least 30 min between subjects). The doses in these cohorts in younger 
adults must be lower than doses that have shown acceptable tolerability in younger adults 
(based on the data from 12 subjects up until 48 h after the first dose). The same dose will 
not be administered twice, i.e., in two cohorts. 
For BNT162b1 and BNT162b2, administration of the planned 10 µg dose in older subjects 
(Cohort 8) may start once at least a 30 µg dose has shown acceptable tolerability in 
younger adults (based on the data from 12 subjects up until 48 h after the boost dose). 
The dose in Cohort 8 must also be confirmed by the SRC. In Cohort 8, 12 subjects will be 
dosed using a sentinel dosing/subject staggering (2-4-6) process with intervals of at least 
1 h between the first 6 subjects and then at least 30 min intervals for the remaining 
6 subjects. 
For BNT162b1 and BNT162b2, administration of the planned dose escalation cohorts in 
older adults (Cohorts 9 and 10), 12 subjects will be dosed using a sentinel dosing/subject 
staggering (2-4-6) process with intervals of at least 30 min between subjects. The doses 
planned in these cohorts will only be administered if the dose is confirmed by the SRC. 
The doses planned for Cohorts 8 to 10 are defined in Table 2. 
For the unplanned dose de-escalation cohorts, i.e., where the SRC requests the use of a 
reduced dose for safety reasons, 12 subjects may be dosed on one day with intervals of at 
least 30 min between subjects (as for planned de-escalation cohorts). 
Note: BNT162b1 and BNT162b2 are nucleoside modified RNAs, while BNT162a1 and 
BNT162c2 are both non-modified uridine containing RNAs. RNA modification is known to 
impact the extent of innate immune activation at a given dose level, and thus potentially 
the extent of reactogenicity. Therefore, tolerability data obtained with one of the vaccine 
variants of each of these pairs may be potentially informative for the respective other one 
and should be taken in consideration by the SRC for recommendations of lower or interim 
doses. 
In the case that an individual experiences dose limiting toxicities or that the frequency or 
pattern of AEs within a sub-cohort gives cause for concern, the investigator may request 
by phone an ad hoc review by the SRC, at any time, before further doses of a given 
vaccine construct are administered. 
Expansion cohorts: 
Protocol amendment 6.0 implemented three additional cohorts (Cohorts 11, 12, and 13) 
comprising additional 150 trial subjects aged from 18 to 85 years receiving BNT162b2 
only. 
BNT162b2 has entered a Phase II/III evaluation of efficacy, with the intent to support an 
application for marketing authorization. The dosing regimen under investigation is two 
30 µg BNT162b2 doses given ~21 d apart. 
The expansion cohorts are intended to provide a more in-depth characterization of the 
adaptive immune responses induced by BNT162b2, associated vaccine safety, and the 
impact of factors such as subject disposition and dosing posology on humoral and cell-

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Biomarker (in-depth B cell immunity to SARS-CoV-2) Cohort 14: 
Protocol amendment 8.0 implements an additional cohort (Cohort 14) comprising an 
additional 20 healthy subjects aged from 18 to 85 years receiving BNT162b2 only. Two 
30 µg BNT162b2 doses will be given approximately 21 d apart (P/B regimen). 
Cohort 14 is intended to provide for additional characterization of B cell immune responses 
induced by BNT162b2. The planned dose of BNT162b2, two 30 µg BNT162b2 doses 
given 21 d apart, is the same regimen that has already been tested in the dose escalation 
phase of this trial and in more than 25,000 trial subjects (status 20 JAN 2021) in the 
ongoing global Phase I/II/III trial BNT162-02/C4591001 (NCT04368728). 
For the scientific rationale for Cohort 14, see Section 4.2. 
Part B 
Due to changes in the overall clinical development plan, Part B will no longer be 
conducted. 
4.1.1 
Adaptive trial design elements 
Dose de-escalation and escalation rules have been defined in this protocol (see 
Section 6.6.2). 
4.1.2 
Planned number of trial subjects 
See Table 5. 
4.2 
Scientific rationale for the trial design 
The trial design is based on the sponsor’s experience with trials of this type and other 
published trials for vaccine development. 
The chosen trial design reflects discussion and advice from the PEI obtained in two 
scientific advice meetings held in February and March 2020. At these meetings, the PEI 
supported the high-level design of this trial, specifically the staggered approach, single 
dose (single immunization dose) and P/B testing, conditional to performance of lower dose 
exploration if appropriate and re-consideration of the dose regimens for Part B if 
appropriate. 
Part A of the trial is designed as a classical dose escalation, investigating the dose range 
which is most likely to be well tolerated and induce a virus neutralizing response. To 
ensure trial subject safety, a staggered approach has been chosen starting with a defined 
low standard dose. Use of the overlapping escalating doses in Cohorts 1 to 3, i.e., 
progression to initiation of dosing at the next higher dose when data is available for 6 of 
12 trial subjects per group, allows a faster dose escalation while ensuring trial subject 
safety. 
Trial subjects in Cohort 1 (with the FIH immunization), will be immunized using a sentinel 
dosing/staggering of subjects (EMA 2017 guidance “Strategies to Identify and Mitigate 
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The expansion cohorts (Cohorts 11 to 13) are designed to be complementary to the 
ongoing global Phase I/II/III trial BNT162-02/C4591001 (NCT04368728), to demonstrate 
clinical efficacy and safety for two 30 µg BNT162b2 doses given ~21 d apart, which 
enrolled over 40,000 subjects. This Phase I/II/III trial does not include the detailed 
immunogenicity assessments needed to better understand the mode-of-action of the 
vaccine and approaches for potential improvements, e.g., in defined populations (by age, 
gender, immunocompromised status, certain ethnicity-associated HLA, etc.). This trial will 
therefore include such immunogenicity assessments, including detailed characterization of 
immune responses to BNT162b2 in respect of binding antibodies, neutralizing antibodies, 
and cell-mediated immunity (CMI), including evaluation of CD4 and CD8 T-cell responses. 
Cohort 11 aims to determine whether a lower prime dose may further improve vaccine 
tolerability (reactogenicity), without compromising immunogenicity while exploring whether 
this alternative posology promotes a more favorable pattern of composite immune 
response modulation. A lower prime dose may further improve reactogenicity and may 
modulate the pattern of the composite immune response towards a more pronounced 
B-cell response. This alternative posology, if proven effective, could support future ring-
vaccination strategies and substantial dose efficiencies. The latter could be important 
during the scale-up phase at the beginning of a pandemic. It has previously been 
demonstrated for non-RNA vaccines that an asymmetric prime-boost strategy does not 
adversely impact the resulting immunogenicity. The use of a lower prime dose may enable 
optimization of the initial CMI response, when it is most beneficial for acute patient 
protection, without compromising the overall humoral response. This cohort will include 
long term monitoring of the immune response and immune defense. 
Cohort 12 is intended to complement the ongoing Phase II/III evaluation of efficacy by 
including assessment of the immune mechanisms induced by this unique class of vaccine. 
The data from this cohort addresses the expected dynamic range of inter-individual 
variability and could provide insights into treatment success factors and/or development 
strategies for future vaccine candidate design/selection for the current pandemic and 
future COVID-19 outbreaks. This cohort will include long term monitoring of the immune 
response and immune defense. 
Cohort 13 will comprise immunocompromised adults, a population that has a particular risk 
in the current pandemic for contracting COVID-19 and for severe complications. The 
reactogenicity but also the immune response to BNT162b2 may be dampened in 
immunocompromised individuals. This cohort will show whether the immune response is 
indeed compromised and if yes to which extent and in which of its components and thus 
allow rational approaches to also serve this population of subjects. It is crucial that the 
priority vaccination of high risk populations is supported by data demonstrating that 
vaccination will be well tolerated and clinically beneficial. 
BNT162b2 was selected for Phase II/III evaluation of efficacy, in part, due to its superior 
performance in elderly subjects, who typically demonstrate lower reactogenicity than 
younger subjects, but also lower levels of immunogenicity than younger subjects. The 
objective of Cohort 13 is to characterize the immune responses in a population with both 
the age-related lower immunogenicity and the lower immunogenicity linked to being 
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strategies. This cohort will include long term monitoring of the immune response and 
immune defense. 
Cohort 14 will characterize B cell and plasma cell immunity to SARS-CoV-2 after 
vaccination with BNT162b2. Non-clinical in vivo studies with BNT162b2 have indicated 
increased cellularity of follicular germinal centers with increased plasma cells 
(plasmacytosis) in regional lymph nodes after vaccination. At the onset of the COVID-19 
pandemic, longitudinal studies at the DRFZ Berlin assessed the adaptive immune 
response of patients with severe COVID-19, using single cell transcriptomics of 
plasmablasts and SARS-CoV-2-specific T cells. In brief, patients with severe COVID-19 
showed an immune response reflected by a continuous egress of plasmablasts into the 
blood. This response was driven by transforming growth factor beta (TGF-), which drives 
B cells to produce IgA2 antibodies. None of the analyzed antibodies recombinantly 
produced from the plasmablasts were specific for the SARS-CoV-2 S protein, RBD, or 
nucleocapsid phosphoprotein. 
These results suggest the immune response is initially triggered by SARS-CoV-2 but later 
evolved away from viral-directed immune responses, resulting in a chronic immune 
response producing antibodies of unknown specificity. One question is how the adaptive 
immune response in patients with severe COVID-19 differs from individuals in whom a 
productive adaptive immune response is induced by vaccination. Plasmablasts and T cells 
are excellent biomarkers in this context, since they can be genetically traced by their 
immune receptor. In addition, interactions between plasmablasts and T cells as well as the 
cytokine environment during their activation are reflected in gene expression at the single 
cell level. 
Characterization of B cell and plasma cell immune responses to BNT162b2 will 
complement the data on T cell-mediated immunity and immunogenicity. The results may 
help to better understand COVID-19 as well as characterize the mode-of-action of the 
vaccine. 
Part B of the trial will no longer be conducted due to changes in the global clinical 
development plan in a rapidly evolving situation. 
4.3 
Justification for dose 
Given that BioNTech proposes a rapid response scenario to a newly emerged pandemic 
outbreak, sufficient data is currently not available to experimentally validate the dose 
selection and initial starting dose. Therefore, BioNTech proposed a starting dose of 0.1 µg 
(for BNT162c2), 3 µg (for BNT162a1), and 10 µg (for BNT162b1 and BNT162b2) in this 
trial based on non-clinical experience with the same RNAs encoding other viral antigens 
(such as influenza and HIV antigens). Based on preliminary data from this trial, as 
explained below, the planned doses for the BNT162a1 and BNT162c2 vaccine candidates 
were reduced (see Table 1). 
The general safety and effectiveness of uRNA and modRNA platforms have been 
demonstrated in oncological clinical trials with different administration routes (RB_0003-01 
[NCT02410733], SAR441000 [NCT03871348]). Doses of up to 400 µg total uRNA 
administered IV as RNA lipoplex (RNA-LPX) and doses of up to 1,000 µg total naked 

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modRNA administered intratumorally, have not demonstrated signs of unpredictable 
overstimulation of the immune system. 
The BNT162 vaccines will be administered IM as this route has been demonstrated to lead 
to efficient induction of antigen-specific cellular and humoral immunity and in vivo protein 
expression of comparable drug products (as shown by other companies, i.e., Moderna and 
CureVAC). 
The doses planned in this trial were discussed with the PEI in a Scientific Advice Meeting 
on February 6th, 2020. At this meeting, the PEI supported the high-level design of this trial, 
conditional to dose exploration and, if appropriate, re-consideration of the dose regimens 
for Part B. This protocol reflects this advice. 
As discussed in Section 2.3.1, to date, there is very limited clinical experience with 
BNT162 vaccines in human subjects. Reactogenicity is anticipated and considered to 
contribute to the mode-of-action of inducing vaccine immune responses. Initial dose 
ranging studies have suggested AE profiles consistent with previous usage of similar 
constructs in cancer patients, with AEs generally dividing into 2 groups: local injection site 
reactions and systemic flu-like illness. 
As summarized in the BNT162 IB, to date most of the AEs reported after immunization 
with BNT162 vaccine candidates have been mild to moderate in intensity and no SAEs 
have been reported. Fever of severe intensity has been reported. Most AEs were 
managed with simple measures and resolved spontaneously. 
Based on the available clinical and non-clinical data experience, the sponsor expects the 
planned maximal doses (see Table 1) to be safe. 
The doses planned in this trial for older adults (i.e., adults aged between 56 and 85 years) 
reflect clinical data from the ongoing BNT162-01 and BNT162-02 trials with the vaccine 
candidates BNT162b1 and BNT162b2 in younger adults and elderly (adults aged between 
65 and 85 years). After P/B dosing, these doses (10, 20, and 30 µg) showed acceptable 
tolerability in younger adults and in elderly adults. For details, see the BNT162 IB. 
The dosing regimen planned in this trial for the expansion cohorts (Cohort 12 and 13) and 
Cohort 14, two 30 µg BNT162b2 doses given ~21 d apart (P/B regimen), is the dosing 
regimen tested in the ongoing global Phase I/II/III trial BNT162-02. Status 20 JAN 2021, 
more than 25,000 trial subjects have been dosed with 30 µg BNT162b2 P/B. 
Cohort 11 will explore an alternative posology with low-dose prime (3 µg) and standard 
dose boost (30 µg) as described elsewhere. 
Taken together, the planned starting doses in this trial are considered to be safe, but still 
sufficient to induce an antiviral immune response. 
4.4 
End of treatment (EoT) and end of trial definition 
A trial subject is considered to have completed the trial if they have completed all planned 
visits as listed in the SoA, including all follow-up visits (see Section 1.3). 
The EoT is defined as the date the last subject completed the EoT Visit (for BNT162c2 
given SD Visit 6, for all cohorts with P/B dosing Visit 7). 

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The end of trial is defined as the date when the last subject completed the last planned 
visit given in the SoA (see Section 1.3). The trial may end earlier if there are no remaining 
subjects from Cohorts 11 to 13 for the 2-year follow-up period (see Table 8); subjects who 
receive non-trial SARS-CoV-2 vaccinations will be discontinued. 
5 
TRIAL POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
5.1.1 
Inclusion criteria Part A 
Volunteers are only eligible to be enrolled in the trial if they meet all of the following 
criteria: 
1. Have given informed consent by signing the informed consent form (ICF) before 
initiation of any trial-specific procedures. 
2. They must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, lifestyle restrictions (e.g., to practice social distancing and to follow 
good practices to reduce their chances of being infected or spreading COVID-19), and 
other requirements of the trial. 
3. They must be able to understand and follow trial-related instructions. 
4. For younger adult cohorts, volunteers must be aged 18 to 55 years, have a BMI over 
19 kg/m2 and under 30 kg/m2, and weigh at least 50 kg at Visit 0. 
OR 
For older adult cohorts, volunteers must be aged 56 to 85 years, have a BMI over 
19 kg/m2 and under 30 kg/m2, and weigh at least 50 kg at Visit 0. 
OR 
For the immunocompromised adult cohort (Cohort 13), volunteers must be aged 18 to 
85 years, have a BMI over 19 kg/m2 and under 30 kg/m2, and weigh at least 50 kg at 
Visit 0. 
5. They must be healthy, in the clinical judgment of the investigator, based on medical 
history, physical examination, 12-lead ECG, vital signs (systolic/diastolic blood 
pressure, pulse rate, body temperature, respiratory rate), and clinical laboratory tests 
(blood chemistry, hematology, and urine chemistry) at Visit 0. 
Note: Healthy volunteers with pre-existing stable disease, defined as disease not 
requiring significant change in therapy or hospitalization for worsening disease during 
the 6 wks before enrollment, can be included. 
OR 

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For the immunocompromised cohort (Cohort 13); volunteers who have previously 
received solid organ transplant, or peripheral blood stem cell transplantation 
≥6 months after transplantation, or individuals with HIV infection with a CD4+ T-cell 
count of ≥200 x 106/L at Visit 0. Individuals with lower T-cell counts will be excluded 
from the trial on the basis that this represents a significant medical complication. In the 
clinical judgment of the investigator, volunteers must be immunocompromised but 
otherwise healthy. After consultation with the Medical Monitor, this may include 
individuals receiving immunosuppressant therapy due to another confounding disease 
at least 2 wks prior to enrollment and/or at least 6 wks following immunization with 
BNT162b2, and/or individuals with immunosuppressive treatment of an autoimmune 
disease if the disease is stable. 
6. WOCBP must have a negative beta-human chorionic gonadotropin urine test at Visit 0 
and Visit 1. Women that are postmenopausal or permanently sterilized will be 
considered as not having reproductive potential. 
7. WOCBP must agree to practice a highly effective form of contraception during the trial, 
starting after Visit 0 and continuously until 60 d after receiving the last immunization. 
WOCBP must agree to require their male partners to use condoms during sexual 
contact (unless male partners are sterilized or infertile). 
8. WOCBP must confirm that they practiced at least one highly effective form of 
contraception for the 14 d prior to Visit 0. 
9. WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during trial, starting after Visit 0 and continuously until 60 d after receiving 
the last immunization. 
10. Men who are sexually active with a WOCBP and have not had a vasectomy must 
agree to practice a highly effective form of contraception with their female partner of 
childbearing potential during the trial, starting after Visit 0 and continuously until 60 d 
after receiving the last immunization. 
11. Men must be willing to refrain from sperm donation, starting after Visit 0 and 
continuously until 60 d after receiving the last immunization. 
12. They must have confirmation of their health insurance coverage prior to Visit 0. 
13. They must agree to not be vaccinated during the trial, starting after Visit 0 and 
continuously until 28 d after receiving the last immunization. 
5.2 
Exclusion criteria 
5.2.1 
Exclusion criteria Part A 
Volunteers are excluded from the trial if they meet or present any of the following criteria: 
1. Have had any acute illness, as determined by the investigator, with or without fever, 
within 72 h prior to the first immunization. An acute illness which is nearly resolved with 
only minor residual symptoms remaining is allowable if, in the opinion of the 
investigator, the residual symptoms will not compromise their wellbeing if they 
participate as trial subjects in the trial, or that could prevent, limit, or confound the 
protocol-specified assessments. 

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2. Are breastfeeding on the day of Visit 0 or who plan to breastfeed during the trial, 
starting after Visit 0 and continuously until at least 90 d after receiving the last 
immunization. 
3. Have a known allergy, hypersensitivity, or intolerance to the planned IMP including any 
excipients of the IMP. 
4. Had any medical condition or any major surgery (e.g., requiring general anesthesia) 
within the past 5 years which, in the opinion of the investigator, could compromise their 
wellbeing if they participate as trial subjects in the trial, or that could prevent, limit, or 
confound the protocol-specified assessments. See the inclusion criteria 5 for non-
excluded medical conditions for Cohort 13. 
5. Have any surgery planned during the trial, starting after Visit 0 and continuously until at 
least 90 d after receiving the last immunization. 
6. Had any chronic use (more than 21 continuous days) of any systemic medications, 
including immunosuppressants or other immune-modifying drugs (except for 
Cohort 13) within the 6 months prior to Visit 0, unless in the opinion of the investigator 
the medication would not prevent, limit, or confound the protocol-specified 
assessments or could compromise subject safety. 
Note: Healthy volunteers with pre-existing stable disease, defined as disease not 
requiring significant change in therapy or hospitalization for worsening disease during 
the 6 wks before enrollment, can be included. 
7. Had any vaccination within the 28 d prior to Visit 0. 
8. Had administration of any immunoglobulins and/or any blood products within the 
3 months prior to Visit 0. 
9. Had administration of another investigational medicinal product including vaccines 
within 60 d or 5 half-lives (whichever is longer), prior to Visit 0. 
10. Have a known history of active or ongoing hepatitis B or hepatitis C infection; or except 
for Cohort 13: HIV-1 or HIV-2 infection within the 30 d prior to Visit 0. 
11. Have a positive PCR-based test for SARS-CoV-2 within the 30 d prior to Visit 1. 
12. Have a positive drugs of abuse (for amphetamines, benzodiazepines, barbiturates, 
cocaine, cannabinoids, opiates, methadone, methamphetamines, phencyclidine, and 
tricyclic antidepressants) result at Visit 0 or Visit 1. 
13. Have a positive breath alcohol test at Visit 0 or Visit 1. 
14. Previously participated in an investigational trial involving lipid nanoparticles. 
15. Are subject to exclusion periods from other investigational trials or simultaneous 
participation in another clinical trial. When entering the follow-up phase, i.e., after 
completing the EoT visit, subjects are allowed to participate in other clinical trials not 
investigating COVID-19 vaccines or treatments; subjects immunized with BNT162 
vaccines in this clinical trial are allowed to participate in other clinical trials involving 
immunization with BNT162b2. 
16. Have any affiliation with the trial site (e.g., are close relative of the investigator or 
dependent person, such as an employee or student of the trial site). 

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17. Have a history (within the past 5 years) of substance abuse or known medical, 
psychological, or social conditions which, in the opinion of the investigator, could 
compromise their wellbeing if they participate as trial subjects in the trial, or that could 
prevent, limit, or confound the protocol-specified assessments. 
18. Have a history of hypersensitivity or serious reactions to previous vaccinations. 
19. Have a history of Guillain-Barré syndrome within 6 wks following a previous 
vaccination. 
20. Have a history of narcolepsy. 
21. Have history of alcohol abuse or drug addiction within 1 year before Visit 0. 
22. (Except for Cohort 13) Have a history of or suspected immunosuppressive condition, 
acquired or congenital, as determined by medical history and/or physical examination 
at Visit 0. 
23. Have any abnormality or permanent body art (e.g., tattoo) that, in the opinion of the 
investigator, would obstruct the ability to observe local reactions at the injection site. 
24. Have had any blood loss >450 mL, e.g., due to donation of blood or blood products or 
injury, within the 7 d prior to Visit 0 or plan to donate blood during the trial, starting after 
Visit 0 and continuously until at least 7 d after receiving the last immunization. 
25. Have symptoms of COVID-19, e.g., respiratory symptoms, fever, cough, shortness of 
breath and breathing difficulties. 
26. Have had contact with persons diagnosed with COVID-19 or who tested positive for 
SARS-CoV-2 by any diagnostic test within the 30 d prior to Visit 1. 
27. Are soldiers, volunteers in detention, CRO or sponsor staff or their family members. 
28. Regular receipt of inhaled/nebulized corticosteroids (except for Cohort 13). 
29. For older volunteers and for Cohort 13 only: Have a condition known to put them at 
high risk for severe COVID-19, including those with any of the following risk factors: 
− 
Uncontrolled hypertension. 
− 
Diabetes mellitus (HbA1c >8.5% ≥3 months, according to the medical history 
reported by the subject). 
− 
Chronic obstructive pulmonary disease. 
− 
Asthma. 
− 
Chronic liver disease. 
− 
Known Stage 3 or worse chronic kidney disease (GFR <60 mL/min/1.73 m2); 
Except for post-renal transplant patients who should have (estimated) 
GFR ≥40 mL/min/1.73 m2. 
− 
Serious heart conditions, such as heart failure, coronary artery disease, or 
cardiomyopathies. 
− 
Sickle cell disease. 
− 
Cancer (except for Cohort 13). 

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− 
Are immune compromised due to stem cell or organ-transplantation with 
significant medical complications such as acute or chronic graft rejection or 
graft versus host disease requiring intensive immunosuppressive treatment, 
transplant failure, or infectious complications or other conditions that would be 
considered a contraindication for vaccination. 
− 
Are immune compromised due to HIV infection with a CD4+ count of 
<200 x 106/L at screening or significant medical complications such as 
opportunistic infections, malignant complications (e.g., lymphoma, Kaposi 
sarcoma), other organ manifestations consistent with advanced acquired 
immunodeficiency syndrome (AIDS) or other conditions that would be 
considered a contraindication for vaccination. 
− 
Resident in a long term facility. 
− 
Current vaping or smoking (occasional smoking is acceptable). 
− 
History of chronic smoking within the prior year. 
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. 
Trial subjects will be required to practice social distancing and to follow good practices to 
reduce their chances of being infected or spreading COVID-19, e.g., as described in the 
WHO guidance “Protection measures for persons who are in or have recently visited (past 
14 days) areas where COVID-19 is spreading” or regional equivalents. 
Trial subjects will be warned to avoid contact with persons tested positive for SARS-CoV-2 
antibodies or those who have an increased risk for infection. 
Dose ranging (Cohorts 1 to 10) 
For Cohort 1 and any subsequent dose escalation cohort (in younger adults or older 
adults), the first 6 subjects dosed in each group will be required to remain at the site for 
approximately 24 h after the first immunization. The remaining trial subjects in these 
cohorts will be required to remain at the site for approximately 6 h after the first 
immunization. 
For any dose de-escalation or dose-refinement cohorts, i.e., cohorts with doses lower than 
previously tested and found to be acceptable, trial subjects will be required to remain at 
the site for approximately 6 h after the first immunization. 
For all cohorts with P/B dosing (irrespective of whether dose escalation, dose de-
escalation, or dose-refinement cohorts), all trial subjects will be required to remain at the 
site for approximately 6 h after the boost immunization. 
Expansion for BNT162b2 (Cohorts 11 to 13) and Cohort 14 
For Cohorts 11 to 14, all trial subjects will not be required to remain at the site beyond the 
time required for all trial-visit-related procedures to be completed. Care should be taken 
with Cohort 13 subjects (immunocompromised) to minimize the duration of site visits. 

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5.4 
Screen failures 
Screen failures are defined as individuals who consent to participate in the trial but who 
are not subsequently assigned to IMP. 
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 serious AEs (SAEs), if applicable. 
6 
TRIAL TREATMENTS 
Trial treatment is defined as any IMP intended to be administered to a trial subject 
according to the trial protocol. Trial treatment must be administered a physician. 
6.1 
IMP administered 
IMP name: 
BNT162 vaccines - Antiviral RNA vaccines for active immunization against COVID-19 
Type: 
RNA-LNP vaccines utilizing different BioNTech RNA formats, i.e., uRNA (product code 
BNT162a1), modRNA (two variants, product codes BNT162b1 and BNT162b2), 
saRNA (product code BNT162c2) 
Dosage levels: 
See Table 1, Table 2, Table 3, and Table 4. The planned dose per vaccine candidate 
will not exceed the pre-defined maximum dose (see Table 1 and Table 2). The planned 
dose per vaccine candidate will not exceed the listed pre-defined maximum doses. 
Dosage 
frequency: 
One injection or two injections 21 d apart. Injection volumes will be up to 1.5 mL 
Administration 
route: 
Intramuscular (IM); upper arm, musculus deltoideus. For the P/B regimens the same 
arm may be used for both immunizations. The non-dominant arm is preferred. 
 
6.2 
Preparation/handling/storage/accountability 
The preparation of solution for injection will be performed by aseptic handling procedures 
by pharmaceutical personnel or other trained personnel at the trial site. 
For instructions on IMP (BNT162 vaccine) preparation, handling, and storage, see the 
Pharmacy Manual. 
The investigator or a physician must confirm appropriate temperature conditions have 
been maintained during transit for all trial intervention received and any discrepancies are 
reported and resolved before use of the trial intervention. 
Only trial subjects enrolled in the trial may receive IMP and only authorized site personnel 
may administer IMP. 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 
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The investigator, nominated site personnel, or the head of the site (where applicable) is 
responsible for IMP (and any components thereof) accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
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 
Not applicable. 
6.4 
Trial treatment compliance 
Trial subjects will be immunized by a physician. 
The date and time of each immunization 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 
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 during the trial, i.e., starting after Visit 0 and until the respective EoT Visit, must 
be recorded along with the: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Record any vaccination, including SARS-CoV-2 vaccination, received after the EoT Visit 
until the last FU Visit in the CRF. 
The sponsor’s Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Trial subjects must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements), unless, in the opinion of the investigator and 
sponsor, the medication will not compromise their wellbeing, or could prevent, limit, or 
confound the protocol-specified assessments. 
Trial subjects are required to agree to not be vaccinated during the trial, starting after 
Visit 0 and continuously until 28 d after receiving the last immunization (see the inclusion 
criterion 13). 
Trial subjects who receive non-trial SARS-CoV-2 vaccinations will be discontinued from 
the BNT162-01 trial (see Section 7.2). 
Nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., paracetamol/acetaminophen at 
doses of up to 4 g/day is permitted for use any time during the trial. Other concomitant 

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medication may be considered on a case by case basis by the investigator, if required 
after consultation with the sponsor’s Medical Monitor. 
6.5.1 
Premedication 
Not applicable. 
6.5.2 
Rescue medication 
Not applicable. 
6.6 
Dose modifications 
The trial design allows for a flexible dosing which allows a better evaluation on the optimal 
dose range. For details, see Section 4.1. 
The decision to make dose adaptions or to initiate a cohort for each vaccine will be made 
by the SRC (for details, see Section 10.1.5). Dose de-escalation and escalation rules have 
been defined in this protocol (see Section 6.6.2). 
6.6.1 
Dose limiting toxicity 
Applicable to dose ranging cohorts only 
During the time of enrollment into a given dose escalation cohort in Part A, if any of the 
following events occur, it will be considered an individual dose limiting toxicity and further 
dosing in that cohort will be stopped: 
• Anaphylactic reaction considered related. 
• Generalized urticaria considered related. 
• Four trial subjects in that cohort with any severe unsolicited local event, if 
considered related and not manageable with simple measures (e.g., cooling, 
analgesia, nonsteroidal anti-inflammatory drugs [NSAIDs]). 
• AEs within 7 d of vaccination assessed by the investigator to be potentially life-
threatening (Grade 4) and that are possibly related, or for which there is no 
alternative, plausible, attributable cause. 
• Any systemic SAE within 7 d of vaccination that is assessed by the investigator as 
possibly related, or for which there is no alternative, plausible, attributable cause. 
• Any fever >40.0°C (>104.0°F) within 7 d of vaccination considered related and 
confirmed by an investigator or medically qualified person. 
• Two trial subjects (at any dose level) with the same or similar severe (Grade 3 or 
higher) AE (including reactogenicity reported as AEs and clinically significant 
laboratory abnormalities) within 7 d of vaccination, considered related, or for which 
there is no alternative, plausible, attributable cause (for severity grading of AEs see 
Section 10.3.1.7). 

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For the cohorts with BNT162c2 P/B dosing, dosing with the boost dose will only start after 
SRC assessment of Day 28 safety data (solicited and unsolicited) for the cohort testing 
BNT162c2 (SD). 
Approval from the SRC will be required prior to any further dosing in the affected cohort. 
The SRC may call for the opening of a lower dose level cohort. 
The same events will prompt IMP discontinuation for individual subjects as described in 
Section 6.6.4. Tasks connected to the discontinuation of IMP are described in Section 7.1. 
The above guidance regulates how potential dose limiting toxicities may influence the 
decisions to further enroll trial subjects in any cohort. These decisions are taken by the 
SRC based on the 48 h safety data from the first 6 subjects of each cohort (see 
Section 4.1). Due to the staggered sentinel dosing design, subjects will have been 
followed for 4 d for the sentinel subjects when this SRC decision is made. 
The above guidance also regulates how potential dose limiting toxicities may influence the 
decisions to enroll subjects into the next cohort for that vaccine, i.e., to progress to the 
next cohort. These decisions are taken by the SRC based on the 48 h safety data from all 
12 subjects of each cohort (see Section 4.1). Due to the staggered sentinel dosing design, 
subjects will have been followed for 6 d for the sentinel subjects when this SRC decision is 
made. 
The sum of the above events occurring at any time during the trial conduct (i.e., not just 
with 7 d of vaccination) will be used for the overall assessment of the candidate vaccine 
safety profile, i.e., to assess whether any of the observed side effects are possibly linked 
to vaccination. 
The assessment of dose limiting toxicity should be done consistently for all subjects 
treated with the same treatment and dose. 
In addition to data entry in the CRF, dose limiting toxicities (DLTs) will be reported within 
24 h via a SAE Report Form as described in Section 10.3.1.10 and forwarded to the safety 
contacts listed in the same section. 
6.6.2 
Dose modification guidance/rules 
Part A 
See Section 10.1.5 for the data set upon which SRC decisions described below for Part A 
are made. 
• The decision to test reduced or intermediate doses will be made for each vaccine 
independently. 
• Any proposal to alter the planned escalation dose, or to test an additional de-
escalation dose, must be approved by the SRC. 
Dose escalation: 
• Dose escalation will only continue if the previous dose was considered safe and 
well tolerated by the SRC. 

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• Any proposal to alter the planned escalation doses must be approved by the SRC. 
6.6.3 
Mitigation plans for specific AEs 
Based on experience with other BioNTech RNA-based vaccines and published data from 
other RNA-based vaccines, it is anticipated that subjects may experience TEAEs of flu-like 
symptomatology following the administration of RNA vaccines due to the mechanism of 
action of RNA vaccines. This may include fever, chills, rigors, tachycardia, arthralgia, 
myalgia, headache, nausea. Treatment of these events is dependent on the discretion of 
the investigators; however, the following management suggestions are provided: 
• Treat fever with acetaminophen or NSAIDs with a dose per trial site 
recommendation. 
• After the first occurrence of flu-like symptomatology, subjects can be treated with 
standard therapeutic dose of acetaminophen, or NSAIDs, starting at least 2 h after 
the immunization. 
• 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 approximately 2 h 
following the immunization per trial site standard. 
If subjects experience enhanced respiratory disease or progression of flu-like 
symptomatology, such as non-resolution of the symptoms after 7 d, symptom kinetics that 
are inconsistent with a relationship to RNA immunization, additional diagnostic measures 
should be considered and the Medical Monitor should be informed. 
6.6.4 
Safety stopping criteria 
See Section 6.6.1 for the list of events that must prompt discontinuation for the individual 
subjects. 
The SRC will review and evaluate the collected safety data periodically during the trial (see 
Section 10.1.5 for details). A decision to stop treatment for an individual subject or to 
terminate the trial may be taken if safety concerns are identified by the SRC. 
Suspected unexpected serious adverse reactions (SUSARs) will immediately be reviewed 
by the SRC. They will trigger a temporary stop of IMP administration to new subjects in the 
respective dose level cohort for that vaccine until the SRC recommendation to continue or 
to permanently stop IMP administration of new subjects in the respective dose level cohort 
for that vaccine. 
Guidance for discontinuation of trial treatment is provided in Section 7.1. 
6.7 
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 
In rare instances, it may be necessary for a trial subject to permanently discontinue IMP 
administration (i.e., to not receive the boost dose for groups with P/B regimens). If IMP 
administration is definitively discontinued, the trial subject will remain in the trial to be 
evaluated for safety, i.e., subjects should still complete all assessments planned in the 
SoA (Section 1.3). 
IMP administration must be stopped if dose limiting toxicities described in Section 6.6.1 
are observed. 
If any of the above are observed, an unscheduled safety analysis by the SRC will be 
required. Trial subjects who tolerated initial vaccinations will be allowed to receive a 
second vaccination during this time. 
In the event of discontinuation of trial treatment, it must be documented on the appropriate 
CRF/in the medical records whether the participant is discontinuing further receipt of trial 
treatment or also from trial procedures, post-treatment follow-up, and/or future collection of 
additional information. 
7.1.1 
Temporary discontinuation 
For the Cohorts 11 to 14 (inclusive), temporary delays to the boost doses due to 
intercurrent illness (i.e., immunization with the boost dose within 1 wk of the scheduled 
day) are allowed. 
7.1.2 
Rechallenge 
Not applicable. 
7.2 
Trial subject discontinuation/withdrawal from the trial 
A trial subject may withdraw from the trial at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
A trial subject in Cohort 11, 12, or 13 who receives a non-trial SARS-CoV-2 vaccination 
will be withdrawn from follow-up and discontinued from the BNT162-01 trial. 
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. 
If a trial subject withdraws from the trial, he/she may request destruction of any samples 
taken and not tested, and the investigator must document sample destruction in the 
Investigator’s Site File (ISF). 
If the trial subject withdraws consent or is permanently discontinued from the trial, the trial 
subject will be permanently discontinued both from IMP administration and from the trial at 
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If possible, permanently discontinued trial subjects will: 
• Complete all assessments planned for that visit and for the EoT Visit, if 
discontinued on a visit day. 
• Complete all assessments planned for the EoT Visit, if not discontinued on a visit 
day. 
• Subjects permanently discontinued after the EoT Visit will be asked to complete all 
assessments planned for the last planned visit for that cohort as per the SoA (see 
Section 1.3). 
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 and/or should continue in the trial. 
• 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 be replaced to ensure that the 12 subjects 
complete the trial as planned up to Visit 3 for each group unless permanently discontinued 
due to safety issues; in the latter cases, the SRC will decide whether to replace the 
discontinued trial subjects. Trial subjects permanently discontinued after Visit 3 will not be 
replaced. 
8 
TRIAL ASSESSMENTS AND PROCEDURES 
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 (i.e., to administer the boost administration for groups with the 
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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 10.12. 
The listed trial assessments and procedures will be updated to reflect the needs of Part B 
in the planned protocol amendment. 
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). 
8.2.1 
Physical examinations 
Complete physical examinations will be performed at screening. Brief physical 
examinations will be performed at later time points including prior boost immunizations 
(see the SoA in Section 1.3). 
• A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height 
(in cm) will also be measured and recorded during complete physical examinations. 
• 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 
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 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). 
Vital signs should be taken before any blood collection. 

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8.2.3 
Electrocardiograms 
Standard 12-lead ECGs will be recorded at the times given in the SoA (Section 1.3) using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and corrected QT (QTc; according to Bazett) intervals. 
ECGs will be judged by the investigator as clinically significant (yes/no); only the 
investigator assessment and heart rate will be recorded in the CRF. 
8.2.4 
Clinical laboratory tests 
See Section 10.2 for the list of clinical laboratory tests to be performed at the times given 
in the SoA (Section 1.3). 
The investigator must review the laboratory report, document this review with signature 
and date, and record any clinically relevant changes occurring during the trial in the AE 
section of the CRF. 
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 or the sponsor’s Medical 
Monitor. 
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 trial site 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 or dose modification), then the results must 
be recorded in the CRF. 
8.2.5 
Drugs of abuse screening 
Screening for drugs of abuse (amphetamines, benzodiazepines, barbiturates, cocaine, 
cannabinoids, opiates, methadone, methamphetamines, phencyclidine, and tricyclic 
antidepressants) will be performed using a commercially available kit at the times given in 
the SoA (Section 1.3). 
8.2.6 
Testing for alcohol use 
Breath testing for alcohol use will be performed at the times given in the SoA (Section 1.3). 
8.2.7 
Viral screening (for blood-borne viruses) 
The screen will test for: hepatitis B surface antigen, hepatitis B core antibody, hepatitis C 
antibodies, and HIV-1 and HIV-2 antibodies. For SARS-CoV-2 testing, see Section 8.2.10. 

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8.2.8 
Subject diaries 
Trial subjects will be given subject diaries at Visit 1 and be asked to record any reactions 
between visits, solicited local reactions at the injection site (pain, tenderness, 
erythema/redness, induration/swelling) and solicited systemic reactions (nausea, vomiting, 
diarrhea, headache, fatigue, myalgia, arthralgia, chills, loss of appetite, malaise, and fever 
[i.e., ≥38°C]). 
Subject diaries may include App-supported electronic documentation in compliance with 
the applicable data protection regulations. 
Trial site personnel will collect subject diaries at the visits given in the SoA (Section 1.3). 
8.2.9 
Assessment of local reactions 
Local reactions after IM immunization will be assessed by the investigator at the times 
given in the SoA (Section 1.3). This information will be used to validate the solicited 
assessment of local reactions in the patient diary and potentially support AE reporting. 
Local reactions (both investigator assessed and solicited in the subject diaries) will be 
graded using criteria based on the guidance given in US FDA Guidance for Industry 
“Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials” for “Local Reaction to Injectable Products” (see the 
section “Assessment of intensity” in Section 10.3.1.11). 
8.2.10 
SARS-CoV-2 testing 
SARS-CoV-2 testing (PCR-based and antibody-based) will be performed at the time points 
provided in the SoA (Section 1.3). 
This includes PCR-based testing for SARS-CoV-2 as an eligibility criterion and blood 
draws for anti-SARS-CoV-2 antibody testing as baseline reference for immunogenicity 
analysis. 
If required, this reference will allow the discrimination between vaccinated and infected 
subjects. 
The screen for SARS-CoV-2 by PCR-based test using oral swipe sample can be 
performed by either a central laboratory or a “point of care” device at the trial site. 
• If a central laboratory is used: Only the SARS-CoV-2 status will be tested and no 
further data will be generated. 
• If a point of care device is used: The most commonly used devices 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. 

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The anti-SARS-CoV-2 antibody testing will be performed with a commercially available 
antibody test. In case this commercial antibody test can, discriminate between vaccine-
specific and infection-specific antibody responses (based on the antigens used), it will be 
used to test subjects who may have experienced enhanced respiratory disease or 
progression of flu-like symptomatology, such as non-resolution of the symptoms after 7 d, 
symptom kinetics that are inconsistent with a relationship to RNA immunization, as might 
be expected with a COVID-19 disease (see Section 6.6.3). 
In these cases, ad hoc anti-SARS-CoV-2 antibody testing will be performed to test for the 
development and presence of SARS-CoV-2-specific antibodies, ideally at approximately 
14 d and 28 d after the last immunization with the BNT162 candidate vaccine. This data 
will be used to evaluate the development and progression of an antibody response 
allowing the diagnosis of a manifest infection. 
In case this commercially available test cannot discriminate between vaccine-specific and 
infection-specific antibody responses, the same kind of analysis will be performed with a 
custom-made assay specifically developed by the CRO. 
8.2.11 
Subject hotline 
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 for specific AEs, see Section 6.6.3. 
8.2.12 
Subject wellbeing questioning 
Structured non-leading subject wellbeing questioning will be performed at the times given 
in the SoA (Section 1.3). Subject responses may trigger more in-depth questioning on 
specific topics, and may trigger diagnostic measures (including ad hoc site visits) at the 
discretion of the investigator. 
8.2.13 
Assessment of systemic reactions 
Systemic reactions after IM immunization will be assessed via daily solicited reports in the 
subject diaries and at the times given in the SoA (Section 1.3). 

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Systemic reactions will be graded using criteria based on the guidance given in US FDA 
Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials” for “Systemic reaction grading scale” (see 
the section “Assessment of intensity” in Section 10.3.1.11). 
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 and remain responsible for 
following up all AEs and SAEs. 
8.3.1 
Time period and frequency for collecting AE and SAE information 
For Cohorts 1 to 10, all AEs and SAEs will be collected from the date of subject consent 
until discharge from the trial only IMP-related AEs and any SAEs will be collected. 
For Cohorts 11 to 13 and 14, all AEs and SAEs will be collected from the date of subject 
consent until Visit 7 (the EoT Visit). From Visit 7 through 9 only IMP-related AEs, SAEs, 
and SARS-CoV-2 infections will be collected. After Visit 9 (e.g., Visits 10, 11, and 12) until 
the last scheduled FU Visit (i.e., when the subject is discharged from the trial), any 
SARS-CoV-2 infections and SAEs will be collected. 
For subjects in Cohorts 11 to 13 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. 
All SAEs (initial and follow-up reports) will be recorded and reported to the sponsor or 
designee within 24 h after becoming aware of the event, as indicated in Section 10.3.1.10. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the trial 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a trial subject has been discharged from the trial, and he/she considers the event 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 and/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/DLTs will be followed until resolution, 
stabilization, the event is otherwise explained, or the trial subject is lost to follow-up (as 

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defined in Section 7.3). Further information on follow-up procedures is provided in 
Section 10.3.1.7. 
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 will 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 of discharge 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 towards 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, Independent Ethics Committees (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 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, urine pregnancy tests will be performed using a commercial kit at the times 
given in the SoA (see Section 1.3). 
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). 

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Pregnancy information will be collected for pregnancies that occurred after the date of the 
first dose of trial treatment until 60 d after the last dose of trial treatment for pregnant 
subjects (or until 60 d after the last immunization of the male subject for pregnant female 
partners). 
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 and/or disease-related outcomes not 
qualifying as AEs or SAEs 
Not applicable, this trial will only enroll healthy trial subjects. 
8.3.8 
Adverse events of special interest 
Enhanced respiratory disease or flu-like symptomatology not resolved after 7 d or with 
symptom kinetics that are inconsistent with a relationship to RNA immunization will be 
considered adverse events of special interest (AESI). 
8.4 
Treatment of overdose 
Any dose of trial treatment above the planned dose specified in this protocol will be 
considered an overdose. 
The sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
• Contact the sponsor’s Medical Monitor immediately. 
• Closely monitor the trial subject for any AE/SAE and laboratory abnormalities (at 
least for 7 d). 
• Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the sponsor’s Medical Monitor based on the clinical evaluation of the trial 
subject. 

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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 have been performed. 
For Part A, the inclusion of 12 subjects per group is considered to be adequate for a safety 
assessment of each vaccine per dose level. The probability to observe a particular TEAE 
with incidence of 15% at least once in 12 subjects per group is 85.8%. 
For the expansion cohorts the probability to observe a particular TEAE with incidence of 
5% at least once in 30 and 90 subjects per group, respectively, is 78.5% and 99.0% 
respectively (see Table 10). 
 
Table 10: 
Probability to observe a particular TEAE at least once 
Number of subjects 
TEAE incidence 
Probability to observe a particular TEAE at least once 
12 
15% 
85.8% 
30 
15% 
99.2% 
 
10% 
95.8% 
 
5% 
78.5% 
90 
15% 
>99.9% 
 
10% 
>99.9% 
 
5% 
99.0% 
TEAE = treatment-emergent adverse event. 
 
9.3 
Analysis sets 
The following analyses sets are defined: 
Analysis set 
Description 
Screened Set 
The Screened Set is defined as all subjects who signed informed consent. 
Safety Set 
The Safety Set is defined as all subjects who received at least one dose of IMP. 
 
9.4 
Statistical analyses 
Statistical analyses will be performed by BioNTech or a designated 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 

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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 and groups may be combined as 
appropriate. 
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. 
Treatment-emergent AEs (TEAEs) are defined in Section 10.3.1.1 and will be summarized 
using the Safety Set. In general, AEs will be analyzed by group (i.e., by type [BNT162a1, 
BNT162b1, BNT162b2, BNT162c2 SD, and BNT162c2 P/B] and dose level) and for each 
immunization, i.e., for: 
• Prime immunization up to 7 d after initial immunization 
• Prime immunization up to boost immunization or 28 d after initial immunization 
(whatever comes first) 
• Boost immunization up to 7 d after boost immunization (only for P/B regimens) 
• Boost immunization up to 28 d after boost immunization (only for P/B regimens) 
• Prime immunization up to 28 d after boost immunization or after prime immunization 
(if no boost was given) 
Additionally, AEs will be summarized for all dose levels combined for each type. 
For each analysis, the number and percentage of subjects reporting at least one AE will be 
summarized by PT nested within SOC for each of the following AE types using the Safety 
Set: 
• Any AE 
• Any AE excluding AEs based on solicited reporting via subject diaries 
• Related AE 

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• Grade ≥3 AE 
• Related Grade ≥3 AE 
• Any SAE 
• Related SAE 
Moreover, the number and percentage of subjects with any AE will be summarized by 
worst grade by PT nested within SOC. 
Local reactions and systemic reactions will be graded using criteria based on the guidance 
given in US FDA Guidance for Industry “Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” (see 
Section 10.3.1.11). 
For each immunization, 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: 
• Any local reactions or systemic reactions 
• Grade ≥3 local reactions or systemic reactions 
The analysis of local and systemic reactions will be repeated with a reduced set of terms 
(called the “comparability analysis”), to facilitate like-for-like comparisons between different 
trials in the clinical development program for BNT162 vaccines. 
Moreover, the number and percentage of subjects reporting at least one local reaction will 
be summarized by worst grade using the Safety Set. 
9.4.3 
Secondary endpoints 
The secondary endpoints are defined in Section 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. 
The scheduled time points for assessment are given in the SoA (see Section 1.3). 
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, vital signs, and ECGs. All safety analyses will be based on the Safety Set and 
will be summarized descriptively by group unless otherwise stated. 

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Clinical laboratory parameters 
The clinical laboratory parameters to be summarized and assessed 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 
US FDA Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” (see Section 10.3.1.11). 
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 
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. 
ECG 
ECG parameters to be summarized and assessed are given in Section 8.2.3. The 
scheduled time points for assessment are given in the SoA (see Section 1.3). 
ECGs will be judged by the investigator as clinically significant (yes/no). 
9.4.6 
Other analyses 
Other analyses will be described in the SAP. 
9.5 
Interim analyses 
The final analysis will be performed once all subjects have completed the EoT Visit as 
defined in Section 1.3. An analysis update will be performed once all subjects will have 
completed the last planned visit. No formal interim statistical analysis will be performed. 
However, preliminary analyses based on all data collected until a pre-defined data cut-off 
date (snapshot analyses) may be performed for each cohort once subjects within a cohort 
will have been followed up for at least 7 d following each dose. 

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9.6 
Data Monitoring Committee 
A DMC is not 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. 
• 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. 

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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. 
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 must be informed that their participation is voluntary. 
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 
using a sponsor-approved ICF 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 re-consented to the most current version of the ICF during their 
participation in the trial. 
Informed consent will be obtained for the use of residual biosamples collected for further 
explorative investigations of the immune response in healthy adults after SD or 
P/B immunization, e.g., using new assays that become available after completion of trial 
conduct. 
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 
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 who withdraw consent must be informed that, unless they agree otherwise, 
any biosamples collected will be destroyed. 

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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 
For Part A, the SRC will be comprised by a sponsor medical representative, the Medical 
Monitor, a sponsor-independent investigator, and a site representative. 
Key roles of the SRC are as follows: 
• Before progression to the next cohort, for each vaccine per cohort/dose level,  
assess the data, decide whether to approve initiation of the next cohort/dose level 
and to confirm the planned dose or define another dose for use. The data assessed 
by the SRC is defined in Section 1.1. 
• After completing its evaluation of the 48 h data for the first 6 subjects per group in 
cohort, the SRC may request a prolongation of the observation period to up to 
Day 7 data for later cohorts or other similar adaptions to protect subject wellbeing. 
• Throughout the trial, assess whether to replace trial subjects permanently 
discontinued due to safety issues. 
• Throughout the trial, approval from the SRC will be required prior to resuming any 
dosing in a “stopped” cohort (see Section 6.6.1). The SRC may call for the opening 
of a lower dose level cohort. 
• SRC may make recommendations on increasing the length of the observation 
periods and additional subject wellbeing calls may be included at the discretion of 
the SRC. 
The SRC will act according to its own written procedures described in a charter, and will 
prepare written minutes of its meetings. 
10.1.6 
Dissemination of clinical trial data 
A final clinical trial report integrating all trial results will be prepared by the sponsor. 
This 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 
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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 
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 provide evidence for the existence of the trial subject and substantiate 
the integrity of the data collected. Source documents are filed in the ISF. 
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). 
Source documents are original documents, data, and records (e.g., hospital records, 
clinical and office charts, laboratory notes, memoranda, 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). 
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. 
The sponsor designee reserves the right to close the trial site or terminate the trial at any 
time for any reason at the sole discretion of the sponsor. Trial sites will be closed upon trial 

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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 TMF. 
10.2 
Clinical laboratory tests 
Blood will be drawn and urine will be collected for clinical laboratory tests at the times 
given in the SoA (Section 1.3). 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count and differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelet count. 

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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. 
Follicle stimulating hormone: 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 patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding that is clinically significant), symptom, or disease (new 
or exacerbated) temporally associated with the use of study intervention. 
• Events after signing ICF and before IMP administration will be handled as AEs. 
• A TEAE is defined as any AE with an onset date on or after the first administration 
of IMP (if the AE was absent before the first administration of IMP) or worsened 
after the first administration of IMP (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 (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs, physical 
examination, 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. 
• Reactogenicity need only be reported as an AE if doing so provides clinically 
significant information not available elsewhere (such as the solicited reactions 
listings), e.g., severe reactogenicity lasting longer than the period of solicitation of 
symptoms in the subject diary. Diagnostic AEs for local and/or systemic 

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reactogenicity, e.g., “injection site reaction” or “flu-like illness”, should generally be 
preferred over AEs reporting of individual signs and symptoms. 
• New conditions or (at the discretion of the investigator) any worsening of a pre-
existing condition detected or diagnosed after Visit 0. 
• 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 reactions 
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. 
10.3.1.4 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under trial, 
death due to progression of disease). 
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. 

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• 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. 
• Is a congenital anomaly or a birth defect. 
• Other situations: 
− 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events 
that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the 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 (SUSARs) 
All suspected adverse reactions related to an IMP (the tested drugs and comparators) 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 and seriousness need to be assessed independently for each AE recorded on the 
CRF. 
SAEs must be reported by the investigator to the sponsor immediately (i.e., no more than 
24 h after learning of the event; see Section 10.3.1.10 for 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 (starting from Visit 0 until 21 d 
after the last immunization or trial subject discharge from the trial, whichever one is later). 
To ensure trial subject safety during the trial, safety will be monitored from Visit 0 
(screening) until at least (approximately) 6 months after the last immunization. 

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• Data pertaining to AEs will be collected during each trial visit either based on the 
trial subject’s spontaneous description or investigator’s inquiry or discovered in the 
course of examinations done during the visit, 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. 
• The investigator will then record all relevant AE information in the CRF and perform 
an assessment on: 
− 
Intensity, see the section “Assessment of intensity” in Section 10.3.1.11 for 
guidance on the assessment of intensity 
− 
Seriousness 
− 
Outcome 
− 
Causal relationship of the AE to the trial treatment 
− 
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 
For subjects in yet to be started cohorts, the assessment of AE and/or SAE intensity 
should be done as described in protocol version 7.0 (which includes amendment 04). 
The assessment of AE and/or SAE intensity should be done consistently for all subjects 
treated with the same treatment and dose. 
All subjects treated in completed cohorts, where the first treatment pre-dates approval of 
the protocol version 5.0 (i.e., including amendment 04), should continue to use the grading 
scheme in the earlier protocol version, such that the same grading scheme is used 
consistently for all subjects given the same treatment and dose. 
Where applicable, retrospective re-mapping of grading from 3-point to 4-point scale will be 
completed prior to database lock, with definitions for mild and moderate intensity events 

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aligned and all events previously graded as severe intensity (on 3-point scale), queried to 
determine whether Grade 3 (severe) or 4 (potentially life-threatening) should be applied. 
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 on 
grading of solicited reactions, please refer to guideline “US 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) 
• Dose reduced 
• Drug interrupted; i.e., interruption of IMP administration during a given visit 
• Drug withdrawn 
• Unknown (e.g., in case the trial subject is lost to follow-up) 
• 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: 

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• 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. 
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) 

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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. 
• 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 (e.g., for trial treatment 
administration) will not be considered as reportable SAE. 
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 

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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 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 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 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 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 is the accidental or intentional use of a drug in an amount (per administration 
or cumulatively) higher than the dose being studied (for the trial treatment) or higher than 
the maximum recommended dose according to the authorized product information (for 
approved concomitant medications). An overdose or incorrect administration of a drug is 
not itself an AE, but it may result in an AE. 
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 till the last FU Visit should be reported as 
an SAE/AE. AEs which are rated as “moderate” or “severe” (according to the criteria 
provided in Section 10.3.1.7) will need to be reported as an SAE. If none of the other SAE 
definitions are deemed suitable, then the SAE criterion of being a “medically important 
event” should be applied (according to the definitions provided in Section 10.3.1.4). An 
SAE form should be completed, including follow-up information, as detailed in 
Section 10.3.1.10 such that an SAE report and narrative can be prepared and distributed. 

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All mild cases of proven COVID-19 cases which do not correspond to seriousness criteria 
will be reported as AEs in the CRF. 
10.3.1.10 
Reporting of SAEs 
All SAEs or DLTs (even if 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 period of observation only have to be reported to 
the sponsor if the investigator suspects a relationship to trial medication or the trial 
procedure. 
SAE reporting to sponsor using a paper form (SAE Report) 
For the period of observation, see Section 8.3.1. 
For any SAE or DLT (even if non-serious), the investigator needs to complete the paper 
Serious Adverse Event Form which must be sent to the sponsor via one of the following 
reporting methods: 
• Safety Report fax no.:  
 
+49 (0) 231 
 
• Safety Report e-mail 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 
SAE 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 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 e-mail: 
 
For medical questions, the sponsor’s Medical Monitor for this trial should be contacted; 
contact details are given in the trial Safety Management Plan. 

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10.4 
Contraceptive guidance and collection of pregnancy 
information 
10.4.1 
Definitions 
WOCBP 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of trial treatment, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP: 
• Premenarchal 
• Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• 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. 
Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
A high FSH level in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with more than 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 
postmenopausal status before trial enrollment. 
10.4.2 
Contraception guidance 
WOCBP must confirm that they practiced at least one highly effective form of 
contraception for the 14 d prior to Visit 0. 

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WOCBP must practice a highly effective form of contraception during the trial, starting after 
Visit 0 and continuously until 60 d after receiving the last immunization. WOCBP must 
agree to require their male partners to use condoms during sexual contact (unless male 
partners are sterilized or infertile). 
Men who are sexually active with a WOCBP and have not had a vasectomy must agree to 
practice a highly effective form of contraception with their female partner of childbearing 
potential during the trial, starting after Visit 0 and continuously until 60 d after receiving the 
last immunization. 
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”. 
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. a 
• Intrauterine hormone-releasing system. a 
• 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 a 
hormonal methods of contraception. 
a Contraception methods that in the context of this guidance are considered to have low user dependency. 
10.4.3 
Collection of pregnancy Information 
Pregnancy information will only be collected after obtaining written informed consent from 
the pregnant female trial subject (or if a male trial subjects’ partner becomes pregnant, 
written informed consent from both). 
Pregnancy information will be collected for pregnancies that occurred after the start of trial 
intervention and until 60 d after the last administration of IMP for pregnant trial subjects (or 
until 60 d after the last administration of IMP to the male trial subject for pregnant female 
partners). 
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 e-mail 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. 

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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 
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 
Men must refrain from sperm donation, starting after Visit 0 and continuously until 60 d 
after receiving the last immunization. 
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 

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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. 
Documentation of all involved trial site personnel performing significant trial-related 
procedures and/or making trial-related decisions must be maintained according to GCP 
and applicable regulatory requirements. 
10.7.3 
Contract research organizations 
Documentation of all involved CROs must be maintained according to GCP and applicable 
regulatory requirements. This includes documentation of any delegation of responsibilities 
to CROs. 
10.7.4 
The sponsor and sponsor’s personnel 
The trial sponsor listed on the title page accepts the responsibilities of the sponsor 
according to GCP and applicable regulatory requirements. 
The sponsor must designate appropriately qualified personnel to advise on trial-related 
topics. The trial site will be provided with contact details for these personnel before any 
trial-related procedure is performed. 
A list of key sponsor personnel involved in the preparation of this protocol and the conduct 
of the trial, including their full names, titles, roles, and responsibilities, must be maintained. 
10.8 
Country-specific requirements 
Not applicable. 

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10.10.4 
Protocol amendment no. 04 
Amendment rationale 
The changes planned by amendment 04 were discussed with the PEI on the basis of the 
submitted protocol version 6.0. Amendment 04 was revised in response to received 
feedback, to yield protocol version 7.0. 
This amendment describes adaption of the protocol to: 
• Allow the assessment of additional intermediate and low dose cohorts for BNT162b 
modRNA vaccine candidates to support identification of a suitable dose for 
Phase II/III evaluation. 
• Allow the assessment of BNT162b1 modRNA vaccine candidate in elderly subjects, 
given its favorable safety, tolerability, and immunogenicity profile in younger adults 
to date and recently available non-human primate immunogenicity data for the 
BNT162b1 and other modRNA vaccine candidates. 
• Plan the assessment of BNT162b2 modRNA vaccine candidate in elderly subjects. 
• Allow the assessment of P/B cohorts for the BNT162c2 saRNA vaccine candidate. 
• Allow revision of safety assessment & dose limiting toxicity criteria. 
• Add additional for blood draws for explorative biomarker/immunogenicity research 
purposes. 
This amendment was issued after some of the planned trial subjects have already been 
enrolled into the trial. 
10.10.5 
Protocol amendment no. 05 
Amendment rationale 
Amendment 05 address feedback obtained from the PEI and the IEC on protocol 
version 7.0. Some changes were also implemented to align data collection and reporting in 
this trial with the data collection and reporting in other trials with BNT162 vaccines 
candidates (to facilitate data merging). 
This amendment will be issued after some of the planned trial subjects have already been 
enrolled into the trial. 
10.10.6 
Protocol amendment no. 06 
Amendment rationale 
Protocol amendment 6.0 implemented three additional cohorts (Cohorts 11, 12, and 13) 
comprising up to additional 150 trial subjects aged from 18 to 85 years receiving 
BNT162b2 only. 
BNT162b2 has entered a Phase II/III evaluation of efficacy, with the intent to support an 
application for marketing authorization. The dosing regimen under investigation is two 
30 µg BNT162b2 doses given ~21 d apart. 

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• Due to the extensive experience and exposure already achieved with BNT162 
vaccine candidates, including that almost 17,000 trial subjects have been dosed at 
least once with BNT162b2 (see Table 10). 
Further changes were implemented to align data collection and reporting in this trial with 
the data collection and reporting in other trials with BNT162 vaccines candidates (to 
facilitate data merging). 
This amendment will be issued after some of the planned trial subjects have already been 
enrolled into the trial. 
10.10.7 
Protocol amendment no. 06 (protocol version 10.0) 
Update rationale 
As requested by the IEC, this update reverses the reductions of the intervals between the 
dosing of trial subjects implemented in protocol amendment no. 06 (protocol version 9.0) 
for Cohorts 1 to 10 and Cohort 13. 
This update will be issued after some of the planned trial subjects have already been 
enrolled into the trial. 
10.10.8 
Protocol amendment no. 07 (protocol version 11.0) 
Update rationale 
This update implements: a change in the sponsor name; deletion of the subject wellbeing 
calls given the available clinical data for BNT162b2; added text to avoid under reporting of 
mild COVID-19 related events arising in the trial; addition of a blood draw for CD4+ T-cell 
counting; removal of outdated content; correction of some errors; updates for clarification; 
updates of outdated data. 
This update will be issued after some of the planned trial subjects have already been 
enrolled into the trial. 
10.10.9 
Protocol amendment no. 08 (protocol version 12.0) 
Update rationale 
This update implements one additional independent cohort (Cohort 14) comprising an 
additional 20 trial subjects receiving BNT162b2. Biomarker data from Cohort 14 are 
intended to provide characterization of B cell and plasma cell immune responses induced 
by BNT162b2, and to allow assessment of the durability of responses induced by 
vaccination in addition to continued follow-up of vaccine safety. 
There is also a change to concomitant medication reporting to allow capture of 
vaccinations, e.g., SARS-CoV-2 vaccinations. 

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10.10.10 
Protocol amendment no. 09 (protocol version 13.0) 
Update rationale 
This update implements changes to the follow-up visits of subjects in Cohorts 11 to 13 who 
receive non-trial SARS-CoV-2 vaccinations. For these subjects, blood samples for 
immunogenicity and cell-mediated immune testing will not be collected, and they will be 
discontinued from the BNT162-01 trial. 
10.11 
Data collection and management 
The trial documentation must be adequate for the reconstruction of the trial. 
10.11.1 
Case report forms 
The CRFs will be completed through use of an electronic data capture (EDC) system. Trial 
site personnel will receive training and have access to a manual for appropriate CRF 
completion. The CRFs will be submitted electronically to the sponsor via the system and 
should be handled in accordance with instructions from the sponsor. 
All CRFs should be completed by designated, trained trial site personnel. CRFs should be 
reviewed, verified, and then electronically signed and dated by the investigator or a 
designee. 
At the end of the trial, the investigator will receive trial subject data for his/her trial site in a 
readable format that must be kept with the trial records. Acknowledgment of receipt of the 
trial subject data will be required. 
10.11.2 
Trial subject reported outcomes 
Not applicable. 
10.11.3 
Data management 
The CRO (see the title page) will be responsible for data management of this trial, 
including quality checking of the data. 
Data entered manually will be submitted to the sponsor through use of an EDC system, 
data extracts and reports. Trial sites will be responsible for data entry into the EDC 
system. In the event of discrepant data, the data management service provider will request 
data clarification from the trial sites, which the trial sites will resolve electronically in the 
EDC system. 
The data management service provider will produce a Trial Data Validation Specification 
document that describes the quality checking to be performed on the data. CRFs and 
correction documentation will be maintained in the EDC system’s audit trail. 
Central laboratory data will be sent directly to the data management service provider. 
System backups for data stored by the sponsor and records retention for the trial data will 
be in accordance with regulatory requirements. 

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10.11.4 
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 is responsible for the timely filing of all essential documents in the 
TMF. 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. 
10.12 
Other data 
10.12.1 
Demographic data 
At screening, the following demographic data will be recorded for all trial subjects: 
• Age (in years/months) 
• Gender (male/female) 
• Ethnic group 
10.12.2 
Medical history 
Medical history information will be recorded for at the times given in the SoA (Section 1.3). 
11 
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