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Stateme
nt 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 RNA Pharmaceuticals
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CLINICAL TRIAL PROTO COL
INCLUDING AMENDMENTS NOS. 01 TO 06
BNT162 -01
Version: 9.0 Date: 05 OCT 2020
Sponsor: BioNTech RNA Pharmaceuticals GmbH
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 165)
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 responsible
person: Özlem Türeci, MD, Chief Medical Officer, BioNTech SE
Sponsor: BioNTech RNA Pharmaceuticals GmbH, An der Goldgrube 12, 55131 Mainz,
Germany
Regulatory identifiers: EudraCT no.: 2020 -001038 -36; ClinicalTrials.gov NCT: 04380701; WHO UTN:
U1111- 1249- 4220
Medical Monitor : The sponsor’s Medical Monitor name and contact information will be provided
separately
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
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1 PROTOCOL SUMMARY
1.1 Trial synopsis
Trial number: BNT162 -01
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 immuno comprom ised adults
Objectives and endpoints
Objectives Endpoints a
Primary objective
(All cohorts)
To describe the safety
and tolerability profiles of
prophylactic BNT162
vaccines in healthy adults after single dose (SD;
prime only) or prime/boost
(P/B) immunization.
• Solicited local reactions at the injection site (pain, tenderness, erythema/redness, induration/swelling) recorded up to 7 d after each
immunization (trial days 8 and 29 ).
• Solicited systemic reactions (nausea, vomiting, diarrhea, headache,
fatigue, myalgia, arthralgia, chills, loss of appetite, malaise, and fever)
recorded up to 7 d after each immunization ( trial days 8 and 29 ).
• The proportion of subjects with at least 1 unsolicited treatment -emergent
adverse event (TEAE):
o For BNT162a1, BNT162b1, BNT162b2, and BNT162c2 (P/B):
occurring up to 21 d after the prime immunization (trial day 22) and
28 d after the boost immunization ( trial day 50).
o For BNT162c2 (SD): The proportion of subjects with at least 1
unsolicited TEAE occurring up to 28 d after the immunization (trial
day 29) .
Secondary objectives
(All cohorts)
To describe the immune response in healthy adults after SD or P/B
immunization measured
by a functional antibody titer, e.g., virus
neutralization test (VNT)
or an equivalent assay
available by the time of trial conduct.
For BNT162a1, BNT162b1, BNT162b2, and BNT162c2 (P/B):
As compared to baseline at 7 and 21 d after primary immunization (trial days 8 and 22) and at 7, 14
b, 21, 2 8, 63, and 162 d after the boost immunization
(trial days 5 to 9):
• Functional antibody responses (titers).
• Fold increase in functional antibody titers.
• Number of subjects with seroconversion defined as a minimum of 4 -fold
increase of functional antibody titers as compared to baseline.
For BNT162c2 (SD):
As compared to baseline at 7, 21, 28, 42, 84, and 183 d after the primary
immunization (trial days 8 to 184):
• Functional antibody responses (titers) .
• Fold increase in functional antibody titers.
• Number of subjects with seroconversion defined as a minimum of 4 -fold
increase of functional antibody titers as compared to baseline.
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Objectives Endpoints a
Exploratory objectives
(All cohorts)
To describe the immune
response in healthy adults after SD or P/B
immunization measured
by an antibody binding assay, e.g., enzyme -
linked immunosorbent
assay (ELISA) or an
equivalent assay available
by the time of trial
conduct.
For BNT162a1, BNT162b1, BNT162b2, and BNT162c2 (P/B)
As compared to baseline at 7 and 21 d after primary immunization (trial days 8 and 22 ) and at 7, 14
b, 21, 28, 63, and 162 d after the boost immunization
(trial days 8 to 184).
• Antibody responses measured (concentrations/titers ).
• Fold increase in antibody (concentrations /titers ).
• Number of subjects with seroconversion defined as a minimum of 4 -fold
increase of antibody concentrations /titers .
For BNT162c2 (SD )
As compared to baseline at 7, 21, 28, 42, 84, and 183 d after the primary immunization ( trial days 8 to 184):
• Antibody responses measured (concentrations) .
• Fold increase in antibody (concentrations) .
• Number of subjects with seroconversion defined as a mi nimum of 4 -fold
increase of antibody concentrations .
(All cohorts)
To describe the cell -
mediated immune (CMI) responses . For BNT162a1, BNT162b1, BNT162b2, and BNT162c2 (P/B) and BNT162c2
(SD)
At baseline and at 28 d after the primary immunization ( trial day 29 ):
• CMI responses measured , e.g., by enzyme- linked immuno -spot (ELISpot)
and intracellular cytokine staining (ICS).
Additional exploratory
objective
(Only for the Expansion
cohorts [Cohorts 11 to
13])
To further characterize
the long term adaptive
immune response after
P/B immunization with 30 µg BNT162b2. As compared to baseline at 7 and 21 d after primary immunization (trial days 8 and 22) and at 7, 14
b, 21, 28, 63, and 162, 343, 525, and 708 d after the
boost immunization ( trial days 8 to 730).
• Functional antibody titers measured (e.g.) using VNT.
o Measured cross -neutralization of viruses from other coronavirus
families.
• Further assays for:
o Antibody -dependent cellular cytotoxicity (ADCC).
o Antibody induced phagocytosis.
o Immune cell degranulation.
o Activation of immune cells such as lymphocytes and granulocytes.
o Antibody mediated uptake and formation of immune complexes.
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Objectives Endpoints a
Additional exploratory
objective s only for the
Expansion
cohort s [Cohorts 11 to
13])
To further characterize
the long term adaptive
immune response after
P/B immunization with 30 µg BNT162b2. As compared to baseline at 364, 546, and 7 29 d after the primary
immunization (trial days 365 to 730):
• Functional antibody titers measured (e.g.) using VNT.
o Antibody responses measured (titers) .
o Fold increase in antibody titers.
o Number of subjects with seroconversion defined as a minimum of 4 -
fold increase of antibody titers.
• Functional antibody binding concent rations measured (e.g.) using ELISA.
o Antibody responses measured.
o Fold increase in antibody titers.
o Number of subjects with seroconversion defined as a minimum of 4 -
fold increase of antibody titers.
• CMI responses measured (e.g.) using ELISpot and ICS.
(Only for the Expansion
cohorts [Cohorts 11 to
13])
To further characterize
the adaptive immune
response: Assessment of
cell-mediated immunity • Further characterization of vaccine and SARS -CoV-2 specific antigen-
specific CD4 and CD8 T -cells, e.g., using ELISpot, ICS.
• Functional characterization of T-cells (e.g. antigen dependent cytokine
secretion, activation, proliferation, cytotoxicity, determination of human
leukocyte antigen [HLA] restriction) .
• Cellular and molecular phenotyping of immune cells using e.g. ,
immunophenotypic characterization of T-cells to define reactive T -cell
subsets .
• Bulk or single cell T-cell receptor (TCR ) and transcriptome sequencing,
quantitative polymerase chain reaction (qt -PCR ) studies to profile and
characteri ze and track TCRs and quantify the number of antigen -specific
T-cells.
a) The given days are approximate; the respective schedule of activities defines assessment windows.
b) Only cohorts starting prime dosing after approval of amendment 09.
The additional exploratory objectives apply for subjects included in the expansion cohorts
in addition to all primary, secondary, and exploratory endpoints defined for other trial
subjects.
Trial 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 objective originally described
for Part B have been implemented in the ongoing development via a pivotal Phase I/II/III
trial BNT162 -02/C4591001 (ClinicalTrials.gov NCT: 04368728).
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.
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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 tria l BNT162 -02/C4591001 (ClinicalTrials.gov NCT: 04368728). Therefore, for
BNT162b2, amendment 09 of this trial introduces 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 posol ogy and explor ing an alternative posology .
The chosen trial design reflects discussion and advice from the Paul -Ehrlich Institute (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 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 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 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
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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 15 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
15 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 15 min between subjects) . The doses in these cohorts in younger
adults must be lower than doses 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 µ g dose in older subjects
(Cohort 8) may start once at least a 30 µ g 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
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staggering (2-4- 6) process with interva ls 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 15 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
inves tigator 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 cohort s (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 tw o
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 -
mediated immunity. These cohorts will extend the safety data of BNT162b2 to a broader trial population and thus closer to the vaccine target population.
Moreover, each of these cohorts will add to a more differentiated understanding of the
BNT162b2- induced adaptive immune response composed of antigen- specific anti bodies,
CD4 and CD8 T- cells, with a view to developing insights into the mechanisms by which
immunity to SARS- CoV- 2 may be induced and factors driving any variability in response.
Alternative treatment approaches for difficult t o treat or high risk subjects may be
determined . In each of these dose cohorts , a broader characterization of T- cell and
antibody responses and their inter -individual variation will be performed. This will include
the characterization of the dependency of adaptive immune responses on factors such as age, HLA haplotype, body mass index ( BMI) and gender .
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
almost 17,000 adult subjects , including those with acute and chronic illnesses, in the
ongoing global P hase I/II/III trial BNT162 -02/C4591001 (ClinicalTrials.gov NCT:
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04368728) . As such, all trial subjects in the three expansion cohorts can be treated in
parallel .
For Cohort 13, the interval between prime immunizations will be at least 15 min. For prime
immunization in Cohorts 11 and 12 and for all cohorts after the boost immunization, the
interval will be at least 5 min.
The three expansion cohorts (with comparable numbers of male and female subjects for each of the defined age groups, see the section Population below) are as follows:
• Cohort 11: Alternative posology cohort with 30 healthy adults who will receive
BNT162b2 using one 3 µg prime dose and one 30 µ g boost dose of BNT162b2
given approximately 21 d apart (P/B regim en).
• Cohort 12: Adaptive immune response cohort (including safety and long term
immune response) with 90 healthy adults who will receive two 30 µg BNT162b2
doses given approximately 21 d apart (P/B regimen).
• 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 rational 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 cr oss-contaminat ion of immunocompromised
individuals with high risk pathogens should be followed for 24 months after the primary
immunization.
Part B
Due to changes in the overall clinical development plan, Part B will no longer be
conducted.
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Table 1: Dose ranging : vaccine dose regimens for younger adult s aged 18 to 55 years in Part A (Cohorts 1 to 7)
Vaccine /
mRNA type Vaccine-encoded antigen Vaccine IM
dosing regimen Part A – Cohort numbers & Dose (µg) (12 subjects per cohort)
1
Starting
dose 2
3
De-escalation
dose 4
5
Optional de -
escalation dose 6
7
BNT162a1 /
uRNA RBD of the SARS -CoV-2
S protein Prime: Day 1
Boost: Day 22 1A
3 µg b 2A
0.6 µg a 3A
0.1 µg 4A a
2 µg e 5A
0.3 µg 6A
1 µg
BNT162b1 /
modRNA RBD of the SARS -CoV-2
S protein Prime: Day 1
Boost: Day 22 1B
10 µg 2B
30 µg 3B
1 µg 4B
60 µg d 5B
50 µg 6B
3 µg 7B
20 µg
BNT162b2 /
modRNA Modified version of the full
length SARS -CoV-2 S protein Prime: Day 1
Boost: Day 22 1C
10 µg 2C
30 µg 3C
1 µg 4C a
60 µg d 5C a
20 µg 6C a
3 µg 7C a
50 µg
BNT162c2 /
saRNA Modified version of the full
length SARS -CoV-2 S protein Prime only: Day 1 1D
0.1 µg 2D
0.3 µg 3D
0.1 µg to <3 µg c 4D
1 µg 5D a
0.6 µg 6D a
3 µg d
BNT162c2 /
saRNA Modified version of the full
length SARS -CoV-2 S protein Prime: Day 1
Boost: Day 22 1E
0.1 µg 2E a
0.3 µg 3E
1 µg 4E a
3 µg 5E a
0.6 µg 6E a
5-10 µg d 7E
5-10 µg
a All dose escalation doses used must be judged acceptable by the Safety Review Committee (SRC) before use.
b Status 08 JUN 2020: This cohort was set on hold by the SRC after 6 subjects had been received their Day 1 dose, furthermore the SRC decided not to perform Day 22 dosing for these 6 subjects.
Due to this hold, the starting dose is also the maximum dose.
c Specific doses to be defined, but in the range given. Already given doses will not be repeated.
d The planned maximum doses per vaccine candidate.
e Dosing with this vaccine variant has been put on hold. Dosing may be resumed if disease prevention data for the other vaccine candidates suggest the need for additional vaccine candidates.
IM = intramuscular; RBD = Receptor Binding Domain; S protein = SARS-CoV-2 sp ke protein: tbd = to be defined.
Note: Currently, dosing with BNT162a1 has been deferred. Dosing may be resumed if disease prevention data for the other vaccine
candidates suggest the need for additional vaccine candidates.
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Table 2: Dose ranging : vaccine dose reg imens for older adult s aged 56 to 85 years in Part A (Cohorts 8 to 10)
Vaccine / mRNA type Vaccine-encoded antigen Vaccine IM dosing
regimen Part A – Cohort numbers & Dose (µg) (12 subjects per cohort)a
8
Older adults 9
Older adults 10
Older adults
BNT162b1 / modRNA RBD of the SARS -CoV -2 S protein Prime: Day 1
Boost: Day 22 8B
10 µg 9Ba
20 µg 10Ba
30 µg
BNT162b2 / modRNA Modified version of the full length SARS -
CoV-2 S protein Prime: Day 1
Boost: Day 22 8C
10 µg 9Ca
20 µg 10Ca
30 µg
a All dose escalation doses used must be judged acceptable by the Safety Review Committee (SRC) before use.
IM = intramuscular; RBD = Receptor Binding Domain; S protein = SARS-CoV-2 sp ke protein.
Note: The doses planned in this trial for older adults (i.e., adults aged between 55 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 (aged between 18 and 55 years) and elderly (adults aged between 65 and 85 years). For details, see the BNT162
IB.
BNT162b1:
• BNT162b1 P/B doses of 1, 10, 30, and 50 µg showed acceptable tolerability in younger adults.
• Based on the tolerability profile after the prime dose at 60 µ g (BNT162-01 trial) and 100 µ g (BNT162-02 trial), the respective boost doses were not administered.
• BNT162b1 P/B doses of 10, 20, and 30 µ g showed acceptable tolerability in elderly ad ults. This tolerability appears to be better than seen in younger adults at the same doses.
BNT162b2:
• BNT162b2 P/B doses of 1, 10, and 30 µ g showed acceptable tolerabili ty in younger adults.
• BNT16 2b2 P/B doses of 10, 20, and 30 µg showed acceptable tolerability in elderly adults. This tolerability appears to be better than seen in younger adults at
the same doses.
Based on the tolerability data summarized above, and the implemented safety measures (sentinel/staggered subject dosing, post -dose observations period, wellbeing questioning,
etc.) as described in the s ection Risk assessment , the planned doses in older subjects in this trial are expected to show acceptable tolerability.
Based on the available immunogenicity data after dosing with BNT162b1 and BNT162b2 in younger adults in the BNT162-02 trial (see the BNT162 IB ), the doses planned in this
trial in older subjects are expected to show lower but measurable immunogenicity than in younger adults .
Altogether, the doses planned in older subjects in this trial are considered adequate to support the trial objectives and to pose an acceptable risk to trial subjects.
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Table 3: E xpansion cohorts for BNT162b2 (age 18 to 85 years) in Part A (Cohorts 11 to 13)
Vaccine / mRNA type Vaccine-encoded antigen Vaccine IM
dosing regimen Part A -–- Cohort numbers & Dose (µg) (number subjects per cohort)
11C
(N = 30)
Healthy adults
(Alternative posology) 12C
(N = 90)
Healthy adults
(Adaptive immune response
cohort) 13C
(N = 30)
Immunocompromised but
otherwise healthy adults
(Population expansion cohort)
BNT162b2 / modRNA Modified version of the full
length SARS -CoV-2 S protein Prime: Day 1
Boost: Day 22 3 µg
30 µg 30 µg
30 µg 30 µg
30 µg
S protein = SARS-CoV-2 spike protein.
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Trial duration
In total, the planned trial duration (i.e., the sum of the screening, treatment, and follow -up
phases ) for subjects is expected to be approximately 214 d for Cohorts 1 to 10 and 738 d
Cohorts 11 to 13 .
For logistical reasons, investigation of the different vaccines may not be able to start at the
same time.
Population
Dose ranging Cohorts (Cohorts 1 to 10)
• Healthy adults aged 18 to 55 years (Cohorts 1 to 7; younger adult s) or aged 56 to
85 years (Cohorts 8 to 10; older adult s). Subject s aged 56 to 85 years must be
enrolled such that at least 6 subjects per cohort are aged 65 to 85 years (i.e., are
elderly) .
For each vaccine, 12 subjects are required for each of the dose ranging cohorts .
Expansion cohorts (Cohorts 11 to 13)
• Cohort 11 - Alternative posology cohort : 30 healthy adults aged 18 to 85 years with
comparable numbers of male and female subjects for each of the following age
groups: 18 to 55 years, 56 to 85 years (15 per age group).
• Cohort 12 - Adaptive immune response cohort: 90 healthy adults, with comparable
numbers of male and female subjects for each of the following age groups: 18 to
55 years, 56 to 65 years, and 65 to 85 years (30 per age group).
• Cohort 13 - Population expansion cohort: 30 immunocompromised adults aged 18
to 85 years with comparable numbers of male and female subjects for each of the
following age groups: 18 to 55 years, 56 to 85 years (15 per age group).
Table 4: Overview of the total number of subjects for each vaccine in Part A
Vaccine / mRNA type Vaccine dosing regimen Maximum number of subjects
(assuming all cohorts planned in Table 1, Table 2, and
Table 3 are performed )
BNT162a1 / uRNA Prime/Boost 72 (6 cohorts)
BNT162b1 / modRNA Prime/Boost 120 (10 cohorts)
BNT162b2 / modRNA Prime/Boost 270 (13 cohorts)
BNT162c2 / saRNA Prime only 72 (6 cohorts)
BNT162c2 / saRNA Prime/Boost 84 (7 cohorts)
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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 adul t 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 c ohort (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 ECG, vital signs (s ystolic/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. 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 wit h
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 well being if they
participate as trial subjects in the trial, or that could prevent, limit, or confound the
protocol -specified assessments.
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• 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 re ceiving 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 C ohort 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 or a positive test for any of Hepatitis B, or Hepatitis C, or
(except for Cohort 13) HIV 1 or 2 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 well being if they participate as trial subjec ts 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.
• (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.
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• 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 : Have a condition know n to put them at high risk for severe
COVID- 19, including those with any of the following risk factors:
− Hypertension
− Diabetes mellitus
− Chronic obstructive pulmonary disease
− Asthma
− Chronic liver disease
− Known Stage 3 or worse chronic kidney disease (glomerular filtration rate
<60 mL/min/1.73 m2)
− Serious heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies
− Sickle cell disease
− Cancer (except for C ohort 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 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
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)
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Dosage levels: Part A cohorts:
See Table 1, Table 2, and Table 3. The planned dose per vaccine candidate will not
exceed the listed pre-defin ed 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 visit; Visit 7). 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 w ill 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 - Cohorts 11 to 13 a
a) For the dose regimens, see Table 3.
Figure 1: Graphical depiction of the dose -finding process in Part A
FIH = First -in-humans; h = hour(s); SRC = Safety Review Committee.
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1.3 Schedule of activities
Table 5: Schedule of trial procedures and assessments – BNT162a1, BNT162b1, BNT162b2, and BNT162c2 when tested P/B (excluding Cohorts 11
to 13)
Procedure /
Assessment Visit 0
Visit 1
Pre-dose Visit 1
(Post -)
dosing Visit 2
at
24±2h Phone
call at
48±2h Visit 3
Visit 4
Pre-
dose Visit 4
Dosing
& Post-
dose Phone
call at
48±2h Visit 5
Visit 5a
Visit 6 Visit 7
(EoT
Visit) Visit 8
(FU Visit) Visit 9
(FU Visit)
Day h -30 to 0 1 1 2 8 22 22 29 36 q 43 50 r 85 184
Days to last dose
h 0 0 7 21 0 7 14 21 28 63 162
Informed consent X
Inclusion/exclusion
criteria X X
(review)
Medical history X X
(update)
Physical
examination incl.
height X X a X a X a X a
X a
X a X a
Vital signs, body
weight c X X X b X X X X b X X X X X
12-lead ECG X X
Urine pregnancy
test for WOCBP X X X
Urine drugs of
abuse screen d X X
Alcohol breath test X X
Urine collection for clinical laboratory
e X X X X X X
Blood draw for
clinical laboratory
(15 mL) f X X X X X X
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Procedure /
Assessment Visit 0
Visit 1
Pre-dose Visit 1
(Post -)
dosing Visit 2
at
24±2h Phone
call at
48±2h Visit 3
Visit 4
Pre-
dose Visit 4
Dosing
& Post-
dose Phone
call at
48±2h Visit 5
Visit 5a
Visit 6 Visit 7
(EoT
Visit) Visit 8
(FU Visit) Visit 9
(FU Visit)
Day h -30 to 0 1 1 2 8 22 22 29 36 q 43 50 r 85 184
Days to last dose
h 0 0 7 21 0 7 14 21 28 63 162
Blood draw for viral
screening g X
(5 mL)
Blood draw for
SARS-CoV-2
testing k X
(2.6 mL)
Oral swipe for
SARS-CoV-2
testing X m
Allocation to IMP X
Immunization X l X
Blood draw for immunogenicity
(10 mL)
n X X X X X X X X X
Blood draw for
HLA X (4 mL EDTA-blood) p
Blood draw for CMI
(100 mL) n, o X X
Blood draw for
research X
(≤100 mL) X
(≤50 mL) X
(≤50 mL)
Subject hotline
availability Start => => => => => => => => => => => End
Issue subject diaries X X X X X X X
Collect subject diaries X
X i X X X X X X
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Procedure /
Assessment Visit 0
Visit 1
Pre-dose Visit 1
(Post -)
dosing Visit 2
at
24±2h Phone
call at
48±2h Visit 3
Visit 4
Pre-
dose Visit 4
Dosing
& Post-
dose Phone
call at
48±2h Visit 5
Visit 5a
Visit 6 Visit 7
(EoT
Visit) Visit 8
(FU Visit) Visit 9
(FU Visit)
Day h -30 to 0 1 1 2 8 22 22 29 36 q 43 50 r 85 184
Days to last dose
h 0 0 7 21 0 7 14 21 28 63 162
Record AEs since
last visit X X X X X X X X X j X j
Local reaction
assessment/
systemic events X b X X X X b
X
X X
Concomitant
medication X X X X X X X X
Subject wellbeing questioning X
i X i
a B rief (s ymptom-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 Flex bility 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±9d.
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.
k Blood draw for anti- SARS-CoV-2 ant bodies (samples will be stored until a test is commercially available).
l For Cohorts 1 and 8, i mmunization with at least 1 h interval s between subjects for the first 6 subjects and then with of at least 30 min intervals for the remaining 6 subject. For all other cohorts ,
immunization with at least 15 min intervals between subjects and for the boost injections.
m Oral swipe for SARS-CoV-2 testing either on Day -1 or at the Visit 1 on Day 1.
n The listed blood draw days may be adapted if justified by the collected data. Leftover blood after completion of the immunogenicity assessments may be used for additional analyses as descr bed in
Section 8.7 (Genetics) and/or Section 8.8 (Biomarkers).
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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.
Notes:
If the boost dose is not administered or if trial subjects permanently discontinued from IMP administration, subjects will complete all assessments planned for that visit and for the EoT Visit as listed in the
SoA.
The additional Visit 5a added by protocol amendment 06 will only apply for subjects who give consent.
Abbreviations : AE = adverse event; CMI = cell -mediated immune testing; 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); SARS -CoV- 2 = the virus leading to COVID- 19; WOCBP =
women of childbearing potential.
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Table 6: Schedule of trial procedures and assessments – BNT162c2
Procedure/Assessment Visit 0
Visit 1
Pre-dose Visit 1
Dosing &
Post -dose Visit 2
at 24±2h Phone
call at
48±2 h Visit 3
Visit 4
Visit 5 Visit 6
(EoT Visit) Visit 7
(FU Visit) Visit 8
(FU Visit)
Day a -30 to 0 1 1 2 8 22 29 43 q 85 184
Informed consent X
Inclusion/exclusion criteria X X (review)
Medical history X X
(update)
Physical examination incl.
height X X b X b X b X b X b X b
Vital signs, body weight c X X X d X X X X X
12-lead ECG X X
Urine pregnancy test (for WOCBP) X X X
Urine drugs of abuse screen e X X
Alcohol breath test X X
Urine for clinical laboratory f X X X X X X
Blood draw for clinical laboratory
g X
(15 mL) X
(15 mL) X
(15 mL) X
(15 mL) X
(15 mL) X
(15 mL)
Blood draw for viral screening
h X (5 mL)
Blood draw for SARS-CoV -2
testing i X
(2.6 mL)
Oral swipe for SARS-CoV -2
testing j X
Allocation to IMP X
Immunization k X
Blood draw for immunogenicity X (10 mL) X (10 mL) X (10 mL) X (10 mL) X (10 mL) X (10 mL) X (10 mL)
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Procedure/Assessment Visit 0
Visit 1
Pre-dose Visit 1
Dosing &
Post -dose Visit 2
at 24±2h Phone
call at
48±2 h Visit 3
Visit 4
Visit 5 Visit 6
(EoT Visit) Visit 7
(FU Visit) Visit 8
(FU Visit)
Day a -30 to 0 1 1 2 8 22 29 43 q 85 184
Blood draw for HLA testing p X (4 mL EDTA-blood)
Blood draw for CMI testing
(100 mL) l, m X X
Blood draws for research X
(≤100 mL) X
(≤50 mL) X
(≤50 mL)
Subject hotline availability Start => => => => => => => => End
Issue subject diaries X X X X X
Collect subject diaries X X o X X X X
Record AEs since last visit X X X X X X X n X n
Local reaction assessment /
systemic events X d X X X X
Concomitant medication X X X X X X X
Subject wellbeing questioning X o
a Flex bility 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 85±7 d; Visit 8 Day 184±9d.
b Brief (s ymptom-directed) physical examination; no height measurement.
c Vital signs: systolic/diastolic blood pressure, pulse rate, respiratory rate, and body temperature; body weight only Visit 0.
d At 1, 3, and 6 h (±15 min) after immunization.
e Urine screening for drugs of abuse (amphetamines, benzodiazepines, barbiturates, cocaine, cannabinoids, opiates, methadone, methamphetamines, phencyclidine, tricyclic antidepressants).
f 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.
g 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.
h Viral screening for human immunodeficiency virus (HIV) 1 or 2, hepatitis B, hepatitis C.
i Blood draw for anti- SARS-CoV- 2 ant bodies.
j Oral swipe for SARS-CoV-2 testing either on Day -1 or at the Visit 1 on Day 1.
k For Cohort 1, immunization with at least 1 h intervals between subjects for the first 6 subjects and then with at least 30 min intervals for the remaining 6 subjects. For all other cohorts, immunization
with 15 min intervals between subjects.
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l The listed blood draw days may be adapted if justified by the collected data. Leftover blood after completion of the immunogenicity assessments may be used for additional analyses as descr bed in
Section 8.7 (Genetics) and/or Section 8.8 (Biomarkers).
m For subjects who have given consent, one aliquot of the blood sample drawn for analysis of CMI may be used for human leukocyte antigen typing to allow additional analysis of T -cell receptor repertoire
and / or phenotypic characterization of T- cells specific to vaccine -encoded antigens.
n Only IMP-related AEs and any SAEs.
o O nly 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.
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.
Abbreviations : AE = adverse event; CMI = cell -mediated immune testing; 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); SARS-CoV-2 = the virus leading to COVID-19; WOBCBP = women of childbearing potential.
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Table 7: Schedule of trial procedu res and assessments – Cohorts 11 to 13 (Expansion cohorts only)
Procedure /
Assessment Visit 0
Visit 1
Pre-
dose Visit 1
(Post- )
dosing Visit 2 Visit 3 Visit 4
Pre-
dose Visit 4
(Post -)
dosing Visit 5
Visit 5a
Visit 6 Visit 7
(EoT
Visit) Visit 8
(FU
Visit) Visit 9
(FU
Visit) Visit 10
(FU
Visit) Visit 11
(FU
Visit) Visit 12
(FU
Visit)
Day h -30 to 0 1 1 2 8 22 22 29 36 43 50 r 85 184 365 547 730
Days to last dose h 0 0 1 7 21 0 7 14 21 28 63 162 343 525 708
Informed consent X
Inclusion/ exclusion
criteria X X
(review)
Medical history X X
(update)
Physical exam. incl. height X X
a X a X a X a X a X a X a
Vital signs, body
weight c X X X b X X X X b X X X X X
12-lead ECG X X
Urine pregnancy test
for WOCBP X X X
Urine drugs of abuse
screen d X X
Alcohol breath test X X
Urine collection for clinical lab.
e X X X X X X
Blood draw for clin.
lab. (15 mL) f X X X X X X
Blood draw for viral screening
g X (5 mL)
Blood draw for
SARS-CoV-2 testing
(2.6 mL) k X
Swipe for SARS-
CoV-2 testing X m
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Procedure /
Assessment Visit 0
Visit 1
Pre-
dose Visit 1
(Post- )
dosing Visit 2 Visit 3 Visit 4
Pre-
dose Visit 4
(Post -)
dosing Visit 5
Visit 5a
Visit 6 Visit 7
(EoT
Visit) Visit 8
(FU
Visit) Visit 9
(FU
Visit) Visit 10
(FU
Visit) Visit 11
(FU
Visit) Visit 12
(FU
Visit)
Day h -30 to 0 1 1 2 8 22 22 29 36 43 50 r 85 184 365 547 730
Days to last dose h 0 0 1 7 21 0 7 14 21 28 63 162 343 525 708
Allocation to IMP X
Immunization X l X
Blood draw for
immunogenicity n X
(10 mL) X
(10 mL) X
(10 mL) X
(10 mL) X
(10 mL) X
(10 mL) X
(10 mL) X
(10 mL) X
(10 mL) X
(10 mL) X
(10 mL) X
(10 mL)
Blood draw for HLA X (4 mL EDTA -blood)
Blood draw for CMI (100 mL)
n, o X X X X X X
Blood draw for
research X
(≤100 mL) X
(≤50 mL) X
(≤50 mL)
Subject hotline availability Start => => => => => => => => => => => => => => End
Issue subject diaries X X X X X X X
Collect subject diaries X X X X X X X
Record AEs since last visit X X X X X X X X
j X j X j X j X j
Local reaction
assessment/
systemic events X b X X X X b X
X X
Concomitant medication X X X X X X X X
Subject wellbeing
questioning by
phone 24 h
post-
dose 24 h
post-
dose
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).
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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 Flex bility for visit days: Visit 3 Day 8±1 d; Visit 4 Day 22±2 d; Visit 5 Day 29±3 d; Visit 5.1 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±9d; Visit 10
Day 365±14d; Visit 11 Day 547± 14d; Visit 12 Day 730±14d.
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 Visits 8 and 9, only IMP-related AEs and any S AEs. Visits 10, 11 and 12, only any SAEs.
k Blood draw for anti- SARS-CoV-2 ant bodies (samples will be stored until a test is commercially available).
l For Cohort 13, first immunization with at least 15 min intervals between subjects. For first immunization in Cohorts 11 and 12 and for all cohorts after the boost immunization, immunization with at least
5 min intervals between subjects.
m Oral swipe for SARS-CoV-2 testing either on Day -1 or at the Visit 1 on Day 1.
n The listed blood draw days may be adapted if justified by the collected data. Leftover blood after completion of the immunogenicity assessments may be used for additional analyses as descr bed 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.
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 (including
immunosuppressants).
If the boost dose is not administered or if trial subjects permanently discontinued from IMP administration, subjects will complete all assessments planned for that visit and for the EoT Visit as listed in the
SoA.
Abbreviations : AE = adverse event; CMI = cell -mediated immune testing; 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); SARS -CoV- 2 = the virus leading to COVID- 19; WOCBP =
women of childbearing potential.
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TABLE OF CONTENTS
1 PROTOCOL SUMMARY 2
1.1 Trial synopsis 2
1.2 Schema (graphical representation of the trial) 17
1.3 Schedule of activities 19
TABLE OF CONTENTS 29
LIST OF TABLES 33
LIST OF FIGURES 33
TRIAL -SPECIFIC ABBREVIATIONS/TERMS 34
2 INTRODUCTION 36
2.1 Background 36
2.1.1 Overview of the disease 36
2.1.2 Introduction to BioNTech RNA- based vaccines 36
2.2 Trial rationale 37
2.3 Benefit/risk assessment 40
2.3.1 Risk assessment 40
2.3.2 Benefi t assessment 44
2.3.3 Overall benefit/risk conclusion 45
3 OBJECTIVES AND ENDPOINTS 46
4 TRIAL DESIGN 48
4.1 Overall design 48
4.1.1 Adaptive trial design elements 52
4.1.2 Planned number of trial subjects 52
4.2 Scientific rationale for the trial design 52
4.3 Justification for dose 53
4.4 End of treatment (EoT) and end of trial definition 55
5 TRIAL POPULATION 56
5.1 Inclusion criteria 56
5.1.1 Inclusion criteria Part A 56
5.2 Exclusion criteria 57
5.2.1 Exclusion criteria Part A 57
5.3 Lifestyle considerations 60
5.4 Screen failures 60
6 TRIAL TREATMENTS 62
6.1 IMP administered 62
6.2 Preparation/handling/storage/accountability 62
6.3 Measures to minimize bias: randomization and blinding 62
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6.4 Trial treatment compliance 62
6.5 Concomitant therapy 63
6.5.1 Premedication 63
6.5.2 Rescue medication 63
6.6 Dose modifications 63
6.6.1 Dose limiting toxicity 64
6.6.2 Dose modification guidance/rules 65
6.6.3 Mitigation plans for specific AEs 65
6.6.4 Safety stopping criteria 66
6.7 Treatment after the end of the trial 66
7 DISCONTINUATION OF TRIAL TREATMENT AND TRIAL SUBJECT
DISCONTINUATION/WITHDRAWAL 67
7.1 Discontinuation of trial treatment 67
7.1.1 Temporary discontinuation 67
7.1.2 Rechallenge 67
7.2 Trial subject discontinuation/withdrawal from the trial 67
7.3 Lost to follow -up 68
7.4 Replacem ent of permanently discontinued trial subjects 68
8 TRIAL ASSESSMENTS AND PROCEDURES 69
8.1 Efficacy assessments 69
8.2 Safety assessments 69
8.2.1 Phys ical examinations 69
8.2.2 Vital signs 69
8.2.3 Electrocardiograms 70
8.2.4 Clinical laboratory tests 70
8.2.5 Drugs of abuse screening 70
8.2.6 Testing for alcohol use 71
8.2.7 Viral screening (for blood- borne viruses) 71
8.2.8 Subject diaries 71
8.2.9 Assessment of local reactions 71
8.2.10 SARS- CoV-2 testing 71
8.2.11 Subject hotline 72
8.2.12 Subject wellbeing questioning 72
8.2.13 Assessment of systemic reactions 72
8.3 Adverse events and serious adverse events 73
8.3.1 Time period and frequency for collecting AE and SAE information 73
8.3.2 Method of detecting AEs and SAEs 73
8.3.3 Follow- up of AEs and SAEs 73
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8.3.4 Regulatory reporting requirements for SAEs 74
8.3.5 Pregnancy 74
8.3.6 Death events 75
8.3.7 Disease -related events and/or disease- related outcomes not qualifying as AEs
or SAEs 75
8.3.8 Adverse events of special interest 75
8.4 Treatment of overdose 75
8.5 Pharmacokinetics 75
8.6 Pharmacodynamics 75
8.7 Genetics 76
8.8 Biomarkers (CMI responses, explorative biomarker, immunogenicity research
purposes) 76
8.9 Immunogenicity assessments 77
8.10 Blood collection 78
9 STATISTICAL CONSIDERATIONS 79
9.1 Statistical hypotheses 79
9.2 Sample size determination 79
9.3 Analysis sets 79
9.4 Statistical analyses 79
9.4.1 General considerations 80
9.4.2 Primary endpoints 80
9.4.3 Secondary endpoints 81
9.4.4 Exploratory endpoints 81
9.4.5 Other safety analyses 81
9.4.6 Other analyses 82
9.5 Interim analyses 82
9.6 Data Monitoring Committee 83
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 84
10.1 Regulatory, ethical, and trial oversight considerations 84
10.1.1 Regulatory and ethical considerations 84
10.1.2 Financial disclosure 85
10.1.3 Informed consent process 85
10.1.4 Data protection 85
10.1.5 Committees - SRC 86
10.1.6 Dissemination of clinical trial data 86
10.1.7 Data quality assurance 86
10.1.8 Source documents 87
10.1.9 Trial and site start and closure 87
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10.1.10 Publication policy 88
10.1.11 Protocol preparation and approval 88
10.2 Clinical laboratory tests 88
10.3 Adverse events: Definitions and procedures for recording, evaluating, follow -up,
and reporting 89
10.3.1 Definition of AE and TEAE 89
10.4 Contraceptive guidance and collection of pregnancy information 101
10.4.1 Definitions 101
10.4.2 Contr aception guidance 101
10.4.3 Collection of pregnancy Information 102
10.4.4 Sperm donation 103
10.5 Genetics 103
10.6 Liver safety: Suggested actions and follow -up assessments 103
10.7 Investigators and trial administrative structure 103
10.7.1 Investigators and trial site personnel 103
10.7.2 Trial site personnel assigned trial -related duties 103
10.7.3 Contract research organizations 104
10.7.4 The sponsor and sponsor’s personnel 104
10.8 Country -specific requirements 104
10.9 Other standard abbreviations and definitions 104
10.10 Protocol amendments 105
10.10. 1 Protocol amendment no. 01 105
10.10.2 Protocol amendment no. 02 106
10.10.3 Protocol amendment no. 03 107
10.10.4 Protocol amendment no. 04 107
10.10.5 Protocol amendment no. 05 107
10.10.6 Protocol amendment no. 06 108
10.11 Data collection and management 109
10.11.1 Case report forms 109
10.11. 2 Trial subject reported outcomes 109
10.11.3 Data management 109
10.11.4 Investigator’s Site File and the Trial Master File 110
10.12 Other data 110
10.12.1 Demograp hic data 110
10.12.2 Medical history 110
11 REFERENCES 111
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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) 9
Table 2: Dose ranging: vaccine dose regimens for older adults aged 56 to 85 years in
Part A (Cohorts 8 to 10) 10
Table 3: Expansion cohorts for BNT162b2 (age 18 to 85 years) in Part A (Cohorts 11 to
13) 11
Table 4: Overview of the total number of subjects for each vaccine in Part A 12
Table 5: Schedule of trial procedures and assessments – BNT162a1, BNT162b1,
BNT162b2, and BNT162c2 when tested P/B (excluding Cohorts 11 to 13) 19
Table 6: Schedule of trial procedures and assessments – BNT162c2 23
Table 7: Schedule of trial procedures and assessments – Cohorts 11 to 13 (Expansion
cohorts only) 26
Table 8: Status of ongoing and planned clinical trials (as of 24 SEP 2020) 38
Table 9: Number of trial subjects dosed at least once with BNT162 vaccine candidates in
the ongoing clinical trials (status 24 SEP 2020) 40
Table 10: Probability to observe a particular TEAE at least once 79
Table 11: Local reaction grading scale 98
Table 12: Systemic reaction grading scale 99
Table 13: Fever grading scale 99
Table 14: Laboratory abnormality grading scale 100
LIST OF FIGURE S
Figure 1: Graphical depiction of the dose- finding process in Part A 18
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TRIAL- SPECIFIC ABBREVIATIONS/TERMS
Abbreviation/Term Explanation
Allocated subject Enrolled subjects who are allocated to IMP
BNT162 -02 C4591001 according to the Pfizer trial code
BNT162a BNT162 RNA -LNP vaccine utilizing uRNA (the variant BNT162a1 will be tested in
this trial)
BNT162b BNT162 RNA -LNP vaccine utilizing nucleoside modified mRNA (the variants
BNT162b1 and BNT162b2 will be tested in this trial)
BNT162c BNT162 RNA -LNP v accine utilizing self -amplifying mRNA (the variant BNT162c2
will be tested in this trial)
C4591001 BNT162 -02 according to the BioNTech trial code
CMI Cell-Mediated Immunity
COVID -19 Coronavirus Disease 2019
CRP C-reactive protein
Elderly (adults) As defin ed in ICH E7 , individuals aged 65 years or older
ELISA Enzyme -Linked Immunosorbent Assay
ELISpot Enzyme -Linked Immuno -Spot
Enrolled subjects Subjects who signed an informed consent form, i.e., who gave informed consent
HCS Convalescent human serum
HLA Human leukocyte antigen
IM Intramuscular(ly)
IV Intravenous(ly)
modRNA Nucleoside modified messenger RNA
mRNA Messenger RNA
Older (adults) Defined in this document to be individuals aged 56 to 85 years
P/B Prime/Boost: a dosing regimen, comprising a priming immunization and a boost
immunization
PEI (German) Paul -Ehrlich -Institute
qt-PCR Quantitative polymerase chain reaction
RNA -LNP RNA lipid nanoparticle
RNA -LPX RNA lipoplex
saRNA Self-amplifying messenger RNA
SARS Severe Acute Respiratory Syndrome
SARS- CoV-2 The virus leading to COVID -19
SD Single dose (also referred to as “single priming dose” or “single immunization”)
uRNA Non-modified uridine containing mRNA
VNT Virus neutralization test
Younger (adults) Defined in this document to be individuals aged 18 to 55 years
For standard abbreviations, see Section 10.9.
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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.
The BioNTech SE group is a holding comprising several subsidiaries including BioNTech RNA Pharmaceuticals GmbH, the sponsor of this clinical trial.
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2 INTRODUCTION
2.1 Background
2.1.1 Overview of the disease
Severe Acute Respiratory Syndrome (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).
There are currently no approved vaccines or antiviral drugs to prevent or treat SARS -CoV-
2 infections or its associated disease COVID -19 (Habibz adeh and Stoneman 2020).
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 attenuat ed
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 mos t
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).
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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
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 (see Table 8 ). The status and preliminary
results from all of these are trials are summarized in the following sections.
For the status of ongoing and planned clinical trials, see Table 8 .
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Table 8: Status of ongoing and planned clinical trials (as of 24 SEP 2020)
Trial number Design Current number dosed (subject age)
BNT162-01
(NCT04380701)
Germany Phase I/II, 2 -part, dose escalation
trial.
Part A is open label and non-
randomized.
(All subjects receive active
vaccine)
Part B: Due to changes in the
overall clinical development plan,
Part B will no longer be
conducted. BNT162a1 (age 18 to 55 y ears):
0.1 µg 12 subjects prime / 12 boost
0.3 µg 12 subjects prime / 12 boost
3 µg 6 subjects prime / 0 boost
(Further dosing with BNT162a1 has been deferred)
BNT162b1 (age 18 to 55 y ears):
1 µg 12 subjects prime / 1 2 boost
3 µg 12 subjects prime / 12 boost
10 µg 12 subjects prime / 11 boost
20 µg 12 subjects prime / 11 boost
30 µg 12 subjects prime / 12 boost
50 µg 12 subjects prime / 11 boost
60 µg 12 subjects prime
(Further dosing with BNT162b1 at 60 µg and the boost
dose for already dosed subjects was cancelled)
BNT162b1 (age 56 to 85 y ears):
10 µg 12 subjects prime / 6 boost
20 µg 12 subjects prime / 0 boost
30 µg 2 subjects prime / 0 boost
BNT162b2 (age 18 to 55 years):
1 µg 12 subjects prime / 11 boost
3 µg 12 subjects prime / 12 boost
10 µg 12 subjects prime / 11 boost
20 µg 12 subject s prime / 12 boost
30 µg 12 subjects prime / 12 boost
BNT162b2 (age 56 to 85 y ears):
10 µg 12 subjects prime / 12 boost
20 µg 12 subjects prime / 12 boost
30 µg 12 subjects prime / 2 boost
BNT162c2 SD (age 18 to 55 years):
0.1 µg 12 subjects (single dose)
0.3 µg 12 subjects (single dose)
0.6 µg 12 subjects (single dose)
1 µg 1 2 subjects (single dose)
BNT162c2 P/B (age 18 to 55 y ears):
0.1 µg 12 subjects prime / 12 boost
0.3 µg 12 subjects prime / 12 boost
1 µg 12 subjects prime / 12 boost
3 µg 12 subjects prime / 0 boost
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Trial number Design Current number dosed (subject age)
BNT162-02 /
C4591001
(NCT 04368728)
US, Argentina, Brazil,
Turkey, Germany Phase I/II /III, placebo-controlled,
randomized, observer -blind, dose-
finding trial.
(Subjects are randomized:
4 active vaccine to 1 placebo)
Phase I
BNT162b1 (age 18 to 55 years):
10 µg 15 subjects prime / 15 boost
20 µg 15 subjects prime / 15 boost
30 µg 15 subjects prime / 15 boost
100 µg 15 subjects prime
(Further dosing with BNT162b1 at 100 µg and the boost
dose for already dosed subjects was cancelled)
BNT162b1 (age 65 to 85 years):
10 µg 15 subjects prime / 15 boost
20 µg 15 subjects prime / 15 boost
30 µg 15 subjects prime / 15 boost
BNT162b2 (age 18 to 55 years):
10 µg 15 subjects prime / 15 boost
20 µg 15 subjects prime / 15 boost
30 µg 15 subjects prime / 15 boost
BNT162b2 (age 65 to 85 years):
10 µg 15 subjects prime / 15 boost
20 µg 15 subjects prime / 15 boost
30 µg 15 subjects prime / 15 boost
Phase II-III
BNT162b2 (age 18 to 85 y ears)
30 µg 33,346 subjects (split P/B not available)
(Assuming 50% of the subjects are on BNT162b2
30 µg 16,673 subjects)
BNT162-03
(NCT 04523571)
China Phase I, randomized, placebo -
controlled, observer -blind trial. BNT162b1 (age 18 to 55 years):
10 µg 24 subjects prime / 24 boost
30 µg 24 subjects prime / 24 boost
BNT162b1 (age >55 years):
10 µg 24 subjects prime / 0 boost
30 µg 24 subjects prime / 0 boost
BNT162-04
(NCT 04537949)
Germany Phase I/II, 2 -part, dose escalation
trial.
Part A is open label and non-
randomized.
(All subjects receive active
vaccine) Part B will be defined in a protocol
amendment. BNT162b 3 (age 18 to 55 years):
10 µg 6 subjects prime / 0 boost
BNT162b3 (age 56 to 85 years):
Recruiting.
Note: For the BNT162-02/C4591001 trial, the term “stage” was replaced by “phase” by an amendment.
NCT = ClinicalTrials.gov identify identifier.
See Table 9 for the number of trial subjects dosed at least once with BNT162 vaccine
candidates in the ongoing clinical trials.
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Table 9: Number of trial subjects dosed at least once with BNT162 vaccine candidates in the
ongoing clinical trials (status 24 SEP 2020)
BNT162 vaccine candidate
Dosing regimen (age group) BNT162a1 BNT162b1 BNT162b2 BNT162c2
Phase I
SD (younger adults) 30 177 105 72
SD (older adults) 0 119 81 0
Phase II/III
SD (younger and elderly adults) 16,673*
Total all adults dosed at least once in
Phase I & II/III 30 296 16,859* 72 Sum = 17,257
Sum BNT162b1 + BNT162b2 = 17,155*
* Estimated / includes estimated number based on 1:1 active:placebo assignment.
Older adults = adults aged 56 to 85 y ears; SD = single dose; Younger adults = adults aged 18 to 55 y ears.
For a summary of the available results from the ongoing 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 .
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 F or 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 F or subjects in Cohorts 11 to 13, up to approximately 1022 mL blood will be
drawn per subject over the complete trial, i.e., over approximately 760 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.
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• 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.
• 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 det ails 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 Table 8 and the BNT162 IB ).
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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 adult s seemed
comparable to that recorded in younger adult s 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 adult s in comparison to the
younger adult s 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).
− 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 BNT16 2-02
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 saf ety 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 involve s the first immunization of humans with the BNT162 vaccines,
in the FIH cohorts and all dose escalation cohorts use a sentinel dosing/staggering
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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.
• 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 mont hs 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 II/III trial (from which frequent, rolling safety data
submissions to health authorities are being made) the measures implemented for
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dose ranging cohorts are deemed unnecessary for the expansion cohorts (by
24 SEP 2020, almost 17,000 trial subjects ha ve been dosed at least once with
BNT162b2, see Table 9 ).
• 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.
• 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 t his 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 im muno- compromised populations.
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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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3 OBJECTIVES AND ENDPO INTS
Objectives Endpoints a
Primary objective
(All cohorts)
To describe the safety
and tolerability profiles
of prophylactic BNT162 vaccines in healthy
adults after single dose
(SD; prime only) or
prime/boost (P/B) immunization.
• Solicited local reactions at the injection site (pain, tenderness,
erythema/redness, induration/swelling) recorded up to 7 d after each
immunization (trial days 8 and 29).
• Solicited systemic reactions (nausea, vomiting, diarrhea, headache, fatigue, myalgia, arthralgia, chills, loss of appetite, malaise, and fever) recorded up to 7 d after each immunization (trial days 8 and 29).
• The proportion of subjects with at least 1 unsolicited TEAE:
o For BNT162a1, BNT162b1, BNT162b2, and BNT162c2 (P/B): occurring up to 21 d after the prime immunization (trial day 22) and
28 d after the boost immunization (trial day 50).
o For BNT162c2 (SD): The proportion of subjects with at least 1 unsolicited TEAE occurring up to 28 d after the immunization (trial day
29).
Secondary objectives
(All cohorts)
To describe the immune
response in healthy
adults after SD or P/B
immunization measured
by a functional antibody titer, e.g., VNT or an
equivalent assay available by the time of trial conduct.
For BNT162a1, BNT162b1, BNT162b2, and BNT162c2 (P/B):
As compared to baseline at 7 and 21 d after primary immunization (trial days 8
and 22) and at 7, 14 b, 21, 28, 63, and 162 d after the boost immunization (trial
days 5 to 9):
• Functional antibody responses (titers).
• Fold increase in functional antibody titers.
• Number of subjects with seroconversion defined as a minimum of 4 -fold
increase of functional antibody titers as compared to baseline.
For BNT162c2 (SD):
As compared to baseline at 7, 21, 28, 42, 84, and 183 d after the primary
immunization (trial days 8 to 184):
• Functional antibody responses (titers).
• Fold increase in functional antibody titers.
• Number of subjects with seroconversion defined as a minimum of 4 -fold
increas e of functional antibody titers as compared to baseline.
Exploratory objectives
(All cohorts)
To describe the immune
response in healthy
adults after SD or P/B
immunization measured by an antibody binding
assay, e.g., ELISA or an
equivalent assay
available by the time of trial conduct.
For BNT162a1, BNT162b1, BNT162b2, and BNT162c2 (P/B)
As compared to baseline at 7 and 21 d after primary immunization (trial days 8 and 22) and at 7, 14
b, 21, 28, 63, and 162 d after the boost immunization (trial
days 8 to 184).
• Antibody responses measured (concentrations/titers).
• Fold increase in antibody (concentrations/titers).
• Number of subjects with seroconversion defined as a minimum of 4 -fold
increase of antibody concentrations/titers.
For BNT162c2 (SD)
As compared to baseline at 7, 21, 28, 42, 84, and 183 d after the primary immunization (trial days 8 to 184):
• Antibody responses measured (concentrations).
• Fold increase in antibody (concentrations).
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Objectives Endpoints a
• Number of subjects with seroconversio n defined as a minimum of 4 -fold
increase of antibody concentrations.
(All cohorts)
To describe the CMI
responses . For BNT162a1, BNT162b1, BNT162b2, and BNT162c2 (P/B) and BNT162c2
(SD)
At baseline and at 28 d after the primary immunization (trial day 29):
• CMI responses measured , e.g., by enzyme- linked immuno -spot (ELISpot)
and ICS.
Additional exploratory
objective
(Only for the Expansion cohorts [Cohorts 11 to
13])
To further characterize
the long term adaptive
immune response after P/B immunization with 30 µg BNT162b2. As compared to baseline at 7 and 21 d after primary immunization (trial days 8
and 22) and at 7, 14
b, 21, 28, 63, and 162, 343, 525, and 708 d after the boost
immunization (trial days 8 to 730).
• Functional antibody titers measured (e.g.) using VNT.
o Measured cross -neutralization of viruses from other coronavirus
families.
• Further assays for:
o Antibody -dependent cellular cytotoxicity (ADCC).
o Antibody induced phagocytosis.
o Immune cell degranulation.
o Activation of immune cells such as lymphocytes and granulocytes.
o Antibody mediated uptake and formation of immune complexes.
Additional exploratory objectives only for the
Expansion
cohorts [Cohorts 11 to
13])
To further characterize the long term adaptive immune response after
P/B immuniza tion with
30 µg BNT162b2. As compared to baseline at 364, 546, and 729 d after the primary immunization
(trial days 365 to 730):
• Functional antibody titers measured (e.g.) using VNT.
o Antibody responses measured (titers).
o Fold increase in antibody titers.
o Number of subjects with seroconversion defined as a minimum of 4 -
fold increase of antibody titers.
• Functional antibody binding concentrations measured (e.g.) using ELISA.
o Antibody responses measured.
o Fold increase in antibody titers.
o Number of subjects with seroconversion defined as a minimum of 4 -
fold increase of antibody titers.
• CMI responses measured (e.g.) using ELISpot and ICS.
(Only for the Expansion
cohorts [Cohorts 11 to
13])
To further characterize the adaptive immune
response: Assessment
of cell -mediated
immunity • Further characterization of vaccine and SARS -CoV-2 specific antigen-
specific CD4 and CD8 T -cells, e.g., using ELISpot, ICS.
• Functional characterization of T -cells (e.g. antigen dependent cytokine
secretion, activation, proliferation, cytotoxicity, determination of HLA restriction).
• Cellular and molecular phenotyping of immune cells using e.g., immunophenotypic characterization of T -cells to define reactive T -cell
subsets.
• Bulk or single cell T CR and transcriptome sequencing, quantitative
polymerase chain reaction (qt -PCR) studies to profile and characterize and
track TCRs and quantify the number of antigen -specific T -cells.
a) The given days are approximate; the respective schedule of activities defines assessment windows.
b) Only cohorts starting prime dosing after approval of amendment 09.
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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 objective originally described
for Part B have been implemented in the ongoing development via a pivotal Phase I/II/III
trial BNT162 -02/C4591001 (ClinicalTrials.gov NCT: 04368728).
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 (ClinicalTrials.gov NCT: 04368728). Therefore, for
BNT162b2, amendment 09 of this trial introduces 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 P EI 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 Cohor t 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 15 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 15 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 15 min between subjects). The doses in these cohorts in younger
adults must be lower than doses 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 µ g dose in older subjects
(Cohort 8) may start once at least a 30 µ g 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 15 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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mediated immunity. These cohorts will extend the safety data of BNT162b2 to a broader
trial population and thus closer to the vaccine target population.
Moreover, each of these cohorts will add to a more differentiated understanding of the BNT162b2- induced adaptive immune response composed of antigen- specific antibodies,
CD4 and CD8 T- cells, with a view to developing insights into the mechanisms by which
immunity to SARS- CoV- 2 may be induced and factors driving any variability in response.
Alternative treatment approaches for difficult to treat or high risk subjects may be determined. In each of these dose cohorts, a broader characterization of T- cell and
antibody responses and their inter -individual variation will be performed. This will include
the characterization of the dependency of adaptive immune responses on factors such as age, HLA haplotype, BMI and gender.
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 almost 17,000 adult subjects, including those with acute and chronic illnesses, in the ongoing global Phase I/II/III trial BNT162 -02/C4591001 (ClinicalTrials.gov NCT:
04368728). As such, all trial subjects in the three expansion cohorts can be treated in parallel.
For Cohort 13, the interval between prime immunizations will be at least 15 min. For prime
immunization in Cohorts 11 and 12 and for all cohorts after the boost immunization, the interval will be at least 5 min.
The three expansion cohorts (with comparable numbers of male and female subjects for
each of the defined age groups, see the section Population) are as follows:
• Cohort 11: Alternative posology cohort with 30 healthy adults who will receive
BNT162b2 using one 3 µg prime dose and one 30 µ g boost dose of BNT162b2
given approximately 21 d apart (P/B regimen).
• Cohort 12: Adaptive immune response cohort (including safety and long term
immune response) with 90 healthy adults who will receive two 30 µg BNT162b2
doses given approximately 21 d apart (P/B regimen).
• 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 rational 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 jud gment 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.
Part B
Due to changes in the overall clinical development plan, Part B will no longer be
conducted.
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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 4 .
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, s ingle
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 whil e ensuring trial subject safety.
Trial subjects in Cohort 1 (wit h the FIH immunization), will be immunized using 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 ”).
The expansion cohorts (Cohorts 11 to 13) are designed to be complementary to the ongoing global Phase I/II/III trial BNT162 -02/C4591001 (ClinicalTrials.gov NCT:
04368728) , to demonstrate clinical efficacy and safety for two 30 µg BNT162b2 doses
given ~21 d apart , which will enroll over 40’000 subjects. The 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, 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 whilst 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-
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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 immunocompromi sed 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
immunocompromised. This knowledge could help guide future treatment optimization strategies. This cohort will include long term monitoring of the immune response and immune- defense.
Part B of th e 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 ).
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The general safety and effectiveness of uRNA and modRNA platforms have been
demonstrated in oncological clinical trials with different administration routes (RB_0003-01 N [NCT02410733] , SAR441000 [ NCT03871348] ). Doses of up to 400 µg total uRNA
administered IV as RNA lipoplex (R NA-LPX) and doses of up to 1000 µg total naked
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 6
th, 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 S AEs
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 55 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 µ g) 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 cohort s (Cohort 12 and 13), two
30 µg BNT162b2 doses given ~ 21 d apart (P/B regimen), is the dosing regimen curr ently
being tested in the ongoing global Phase II/III trial BNT162 -02. Status 24 S EP 2020,
almost 17,000 trial subjects have been dosed with 30 µg BNT162b2 P/B .
Cohort 12 will explore an alternative posology with low dose prime (3 µ g) 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.
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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).
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).
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5 TRIAL POPULATION
Prospective approval of protocol deviations to recruitment and enrol lment 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 subject cohorts, volunteers must be aged 18 to 55 years, have a BMI
over 19 kg/m
2 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
OR
For the immunocompromised adult cohort (Cohort 13), volunteers must be aged 18 to 85 years, have a BMI over 19 kg/m
2 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
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. 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
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2 wks prior to enrollment and/or at least 6 w ks follo wing 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 well being if they
participate as trial subjects in the trial, or that could prevent, limit, or confound the protocol- specified assessments.
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.
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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. Received 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 or a positive test for any of Hepatitis B, or Hepatitis C, or HIV 1
or 2 (except for Cohort 13) 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.
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).
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 well being 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.
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19. Have a history of Guillain- Barré syndrome within 6 wks following a previo us
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. Symptoms of COV ID-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.
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:
− Hypertension.
− Diabetes mellitus .
− Chronic obstructive pulmonary disease.
− Asthma .
− Chronic liver disease.
− Known Stage 3 or worse chronic kidney disease (glomerular filtration rate <60 mL/min/1.73 m
2).
− Serio us 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.
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− 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 A IDS 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 d) 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 approx imately 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)
For Cohorts 11 to 13, 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 duration of site visits .
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.
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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.
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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 (2 variants, product codes BNT162b1 and BNT162b2), saRNA
(product code BNT162c2)
Dosage levels: See Table 1, Table 2, and Table 3. The planned dose per vaccine candidate will not
exceed the pre- defined maximum dose (see Table 1 and Table 2 ).
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 Pharm acy 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 site personnel.
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 Mea sures to minimize bias: randomization and blinding
Not applicable.
6.4 Trial treatment compliance
Trial subjects will be immunized by a physician.
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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 EoT Visit , must be recorded
along with the:
• Reas on for use
• Dates of administration including start and end dates
• Dosage information including dose and frequency
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 well being, 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).
Nonsteroidal anti -inflammatory drugs (NSAIDs), e.g., p aracetamol/acetaminophen at
doses of up to 4 g/day is permitted for use any time during the trial. Other concomitant
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 med ication
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 ).
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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 fe ver >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 AE s see
Section 10.3.1.7).
For the cohorts with BNT162c2 P/B dosing, dosing with the boost dose will only start after
SRC assessment of D ay 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.
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The sum of the above events occurring at any time during the trial conduct (i.e., not just
with 7 d of vaccination) will b e 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, DLTs will be reported within 24 h via 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.
• 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 w ith
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.
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• Ensure adequate hydration of trial subjects on the day of immunization. Consider
administering fluids (e.g., water for drinking, 0.5 - 1.0 L) within approximately 2 h
following the immunization per trial site standard.
If subjects experience enhanced respiratory disease or progression of fl u-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 T RIAL
SUBJECT DISCONTINUAT ION/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. For cohorts with P/B dosing, if the boost dose is not administered, 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.
Trial subjects permanently discontinued from IMP administration will complete all assessments planned for that visit and for the EoT Visit as listed in the SoA (Section 1.3).
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.
Trial subjects permanently discontinued from IMP administration will complete all assessments planned for that visit and for the EoT Visit as listed in the SoA (Section 1.3).
7.1.1 Temporary discontinuation
Not applicable. For the Cohorts 11 to 13 (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. Withdrawals are expected to be uncommon.
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).
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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 that time.
If possible, permanently discontinued trial subjects will:
• Complete all assessments planned for that visit and f or the EoT V isit, if
discontinued on a visit day.
• Complete all assessments planned for the EoT V isit, if not discontinued on a visit
day.
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 fol low-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.
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8 TRIAL ASSESSMENTS AN D 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 P/B regimen).
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 perf ormed 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 S oA (Section 1.3). Body weight (in kg) will also be measured and
recorded.
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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.
8.2.3 Electrocardiograms
Standard 12- lead ECG s 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. The laboratory reports must be filed with the source documents.
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).
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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.
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 diar ies 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 solic ited 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 i ntensity ” 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 require d, 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.
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• 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 j ust for SARS- CoV- 2.
Thus, inevitably and automatically, incidental data for the pathogens other than
SARS- CoV-2 will be generated when using such device s. 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.
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 di sease (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
Subject s 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 time 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 Assessm ent 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).
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
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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, all AEs and SAEs will be collected from the date of subject consent until Visit 7. Thereafter, at Visits 8 and 9 only IMP-related AEs and any SAEs will be
collected. At Visits 10, 11, and 12, only any SAEs will be collected.
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.
Investigator s 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 AE s and SAE s 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 /dose limiting toxicities (DLT s) will be
followed until resolution, stabilization, the event is otherwise explained, or the trial subject
is lost to follow -up (as defined in Section 7.3). Further information on follow -up procedures
is provided in 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.
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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 test s will be performed using a commercial kit at the times
given in the SoA (see S ection 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).
Pregnancy information will be collected for pregnancies that occurred af ter 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.
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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 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.
8.5 Pharmacokinetics
Not applicable.
8.6 Pharmacodynamics
Not applicable.
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8.7 Genetics
For Cohorts 1 to 10, a blood sample (blood and / or isolated PBMCs) may be used for HLA
typing of a subject to allow additional analysis, e.g., characterization of TCR repertoire
and/or phenotypic characterization of antigen- specific T -cells as further specified in
Section 8.8 (Biomarkers). Data generated with these additional analyses may provide
information about the HLA dependency of immune response (e.g., if distinct HLA types
have stronger / better immune response towards SARS -CoV- 2).
For Cohorts 11 to 13, a blood sample (blood and / or isolated PBMCs) will be used for HLA
typing of a subject to allow additional analysis. HLA analysis will be conducted in all subjects in the Cohorts 11 to 13.
Further, an additional blood sample may also be used for profiling (e.g. , by use of next
generation sequencing) of TCRs in peripheral blood after vaccination.
Blood samples will only b e used for genetic analysis if the trial subjects have provided
informed consent for this genetic analysis.
Leftover blood after completion of the immunogenicity assessments may be used for the
genetic analyses as described here.
8.8 Biomarkers (CMI responses , explorative biomarker,
immunogenicity research purposes)
Three additional blood draws (with up to 200 mL in total) will be taken at the times listed in
the SoA (Section 1.3) for explorative biomarker/immunogenicity research purposes, these
will be in addition to standard trial assessments in selected dose ranging cohorts, and as
core elements of the assessments of the expansion cohorts.
Research samples will be collected in order to investigate vaccine- induced immune
responses by use of, but not limited to, phenotypic or functional characterization of antigen- specific T -cells (e.g., by flow cytometry -based phenotyping including multimer
staining), analysis of TCR repertoire (e.g., by next generation sequencing) and multiplex -
cytokine analysis.
In addition, samples may be stored and analysis may be performed on biomarker variants thought to play a role in the mechanism of action of BNT162 to evaluate their association with observed clinical responses to BNT162. Furthermore, samples may be used for research to develop methods, assays, prognostics and/or companion diagnostics related to BNT162.
Samples for biomarker analysis will be retained for use for up to 5 years after the end of
the trial. The tube with the sample will be labeled with a number (optionally also with a bar
code) to keep the subject’s identity confidential; the tube label will not include information that could be used to identify the subject. Results of the blood analyses will be linked to the clinical information collected during the trial using this specific number. The analysis will only be carried out on the basis of the label data and samples. Biomarker samples and all data generated using the samples, will be handled in accordance with applicable laws and regulations; this includes requirements applicable for data protection, for sample shipment outside Germany, and a potential withdrawal of consent.
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Blood samples will only be used for biomarker analysis if the trial subjects have provided
informed consent for this biomarker analysis.
8.9 Immunogenicity assessments
Immune responses as laid down in the trial objectives will be assessed at the times listed
in the SoA ( Section 1.3) using:
1) A functional antibody titer determined, e.g., via VNT or an equivalent assay .
• Sero negative is defined as titers below the starting dilution (i.e., below the LOD
[limit of detection] of the assay) .
• Seroconversion after immunization is defined as a 4- fold increase in titer .
o for seronegative pre- immunization sera: a titer ≥ 4-times the LOD.
o for seropositive pre- immunization sera: a titer which is 4-f old higher
than the measured pre- immunization titer.
2) An antibody binding assay, e.g. , ELISA or an equivalent assay .
• Seroconversion after immunization is defined as a 4- fold increase in
titer/antibody concentration.
3) CMI/responses mediated by immune cells such as CD4 and CD8 T- cells and their
functional phenotypic subset by , e.g., ELISpot , ICS, multimer analyses, cytokine
secretion assays , flow cytometry and other tests.
CMI analysis will include among others CD4 and CD8 T -cells, Th1-specific
cytokines ( e.g., IFN -gamma, TNF- alpha, IL- 2, or IL -12) and Th2- specific cytokines
(e.g., IL -4, IL-5, IL-10, IL -13) to analyze the induction of either balanced Th1/Th2
responses , or of unbalanced Th1- dominant or Th2-dominant immune responses ,
respectively .
Additional exploratory analyses of IMP -induced antibody responses with selected samples
may include:
• Assessing neutralization activity against variant spike proteins from other SARS -
CoV-2 strains or other coronavirus families.
• Antibody affinity, isotype and subclass analysis / functional assessment of
antibodies , e.g., ADCC, antibody induced phagocytosis , immune cell degranulation,
activation of immune cells such as lymphocytes and granul ocytes .
• M echanisms that are potentially associated with antibody -dependent enhancement
(ADE) , e.g., antibody mediated uptake of (pseudo) -virus -particles into cells,
formation of immune complexes .
Additional e xploratory analyses of vaccine- induced CMI (including non-T- cell based)
responses with selected samples may include:
• Analysis of immune activation, proliferation, cytotoxicity and cellular , molecular of
immune cells subsets .
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• Bulk or single cell TCR and transcriptome sequencing, qt- PCR studies to profile and
characterize, and track TCRs and to quantify the number of antigen- specific T-cells.
• Analyses of polymorphism in immune response genes .
Correlations will be described – in particular for C ohorts 11 to 13 – between these immune
responses and different subject disposition / characterization parameters such as age,
gender, HLA, in relation to each other with further exploration as scientifically determined.
Instructions on the sample collection, handling, and shipping will be provided in a
Laboratory Manual. The methodology used for these assessments will be documented in the Biomarker Manual.
Leftover blood after completion of the immunogenicity assessments may be used for
additional analyses as described in Section 8.7 (Genetics) and/or Section 8.8
(Biomarkers).
Blood samples will only be used for additional analyses if the trial subjects have provided
informed consent for these additional analyses.
8.10 Blood collection
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.
For subjects in Cohorts 11 to 13, up to approximately 1022 mL blood will be drawn per
subject over the complete trial, i.e., over approximately 760 d.
Additional blood samples may be taken, e.g., for safety assessments after AEs or SAEs .
For enrolled subjects who have not completed the EoT visit (see the SoA in Section 1.3)
before approval of Protocol Amendment 04, the optional additional blood draws added by
protocol amendment 04 will only apply for subjects who give consent.
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9 STATISTICAL CONSIDER ATIONS
9.1 Statisti cal 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%
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 t he
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 tri al 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 (TEAE) 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 immuni zation 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
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• Related AE
• Grade ≥
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