An Exploratory Phase I, Randomized, Observer-blind, Active-controlled, Dose-escalation Trial Evaluating the Safety, Tolerability, and Immunogenicity of an Investigational RNA-based SARS-CoV-2 Vaccine in COVID-19 Vaccine Experienced Healthy Adults
Phase: PHASE1
Conditions: SARS-CoV-2 Infection, COVID-19
Sponsor: BioNTech SE



Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
Tri al n u m b er: B N T 1 6 2 -2 1  
P a g e 3  of 1 1 8  
V er si o n: 8. 0  
D at e: 1 6 S E P 2 0 2 4  
 
 
1  
P R O T O C O L S U M M A R Y  
1. 1  
S y n o p si s  
Tri al titl e  
A n e x pl or at or y P h a s e  I, ra n d o mi z e d , o b s er v er-bli n d, a cti v e -c o ntr oll e d , d o s e -e s c al ati o n  tri al 
e v al u ati n g t h e s af et y, t ol er a bilit y, a n d i m m u n o g e ni cit y of a n i n v e sti g ati o n al R N A -b a s e d S A R S -
C o V -2 v a c ci n e i n C O VI D -1 9  v a c ci n e e x p eri e n c e d h e alt h y a d ult s  
Tri al r ati o n al e  
V a c ci n e s t ar g eti n g t h e s pi k e gl y c o pr ot ei n ( S  pr ot ei n) of s e v er e a c ut e r e s pir at or y s y n dr o m e 
c or o n a vir u s 2 ( S A R S -C o V -2 ) h a v e b e e n u s e d a s a miti g ati o n str at e g y of t h e C or o n a vir u s di s e a s e 
2 0 1 9 ( C O VI D -1 9 ) p a n d e mi c. B N T 1 6 2 b 2 h a s r e c ei v e d a ut h ori z ati o n f or e m er g e n c y s u p pl y, 
c o n diti o n al m ar k eti n g a ut h ori z ati o n, a n d/ or f ull a ut h ori z ati o n i n m or e t h a n 1 0 0  c o u ntri e s gl o b all y 
u n d er t h e tr a d e n a m e “ C O MI R N A T Y”  f or t h e pr e v e nti o n of C O VI D -1 9  c a u s e d b y S A R S -C o V -2 . 
B N T 1 6 2 b 2 , a N 1 -m et h yl p s e u d o uri di n e -n u cl e o si d e -m o difi e d R N A e n c o d i n g t h e S  pr ot ei n  t h at i s 
e n c a p s ul at e d i n li pi d n a n o p arti cl e s ( L N P s ), h a s d e m o n str at e d p ot e nt i m m u n o g e ni cit y, hi g h v a c ci n e 
effi c a c y, a n d a f a v or a bl e s af et y pr ofil e i n P h a s e  I//II/III tri al s, a s w ell a s i n r e al w orl d u s a g e. 
C o n si d eri n g  t h e i n cr e a s e i n t h e n u m b er of v ari a nt s of c o n c er n ( V O Cs ), a s w ell a s t h e n u m b er of 
n e w m ut ati o n s i n t h e S  pr ot ei n i n t h e s e v ari a nt s, a l o n g t er m a n d d ur a bl e i m m u n e r e s p o n s e 
t ar g eti n g c o n s er v e d vir al e pit o p e s c o ul d h el p pr ot e ct i n di vi d u al s fr o m s e v er e s y m pt o m s c a u s e d b y 
e m er g e nt V O C s.  
T h e v al u e of T -c ell r e s p o n s e s a g ai n st n o n -s pi k e pr ot ei n s h a s b e e n e m p h a si z e d b y t h e ri s e of m or e 
a nti g e ni c all y di v er s e V O C s ( e. g., O mi cr o n s u bli n e a g e s, s u c h a s B A. 1, B A. 2 , B A.4 , B A .5 , a n d 
X B B ), w hi c h c a n a v oi d n e utr ali z ati o n vi a m ut ati o n s t o t h e S  pr ot ei n. H o w e v er, t h e r at e of m ut ati o n s 
i n n o n-s pi k e pr ot ei n s i s m u c h l o w er t h a n t h e m ut ati o n r at e o b s er v e d i n t h e S  pr ot ei n . E pit o p e s 
eli citi n g p ot e nt T -c ell r e s p o n s e s h a v e b e e n r e p ort e d t o b e l ar g el y v ari a nt -i n d e p e n d e nt. 
B a s e d o n t h e  r ati o n al e of t ar g eti n g c o n s er v e d e pit o p e s  fr o m m ulti pl e vir al pr ot ei n s t h at eli cit p ot e nt 
T -c ell r e s p o n s e s , Bi o N T e c h i s e v al u at i n g a v a c ci n e c a n di d at e , B N T 1 6 2 b 4 , ai m e d at e n h a n ci n g t h e 
br e a dt h of T -c ell r e s p o n s e s a n d t h e pr ot e cti v e c a p a cit y of s pi k e -b a s e d v a c ci n e s, e s p e ci all y a g ai n st 
s e v er e di s e a s e a n d f ut ur e V O C s . 
B N T 1 6 2 b 4 u s e s t h e s a m e m o d R N A pl atf or m, pr o c e s s e s, a n d L N P f or m ul ati o n a s B N T 1 6 2 b 2, wit h 
t h e R N A c o m p o n e nt s c o m pri si n g a si n gl e R N A e n c o di n g s e g m e nt s of t h e n u cl e o c a p si d a n d 
m e m br a n e pr ot ei n s, a s w ell a s s h ort s e g m e nt s c o nt ai ni n g
 
I n t hi s tri al, B N T 1 6 2 b 4 will eit h er  b e  c o m bi n e d wit h t w o s el e ct e d s pi k e -b a s e d  R N A v a c ci n e s , i. e., 
B N T 1 6 2 b 2 Bi v al e nt ( W T/ O MI  B A. 4/ B A. 5) , h er ei n aft er r ef err e d t o  a s “B N T 1 6 2 b 2 Bi v al e nt ”, a n d 
B N T 1 6 2 b 2 M o n o v al e nt ( O MI X B B. 1. 5) , or gi v e n al o n e . 
•  
B N T 1 6 2 b 4 will b e c o m bi n e d wit h B N T 1 6 2 b 2 Bi v al e nt f or D o s e s  1 a n d 2 f or C o h ort s  1 a n d 
2, a n d D o s e  1 f or C o h ort s  3 a, 3 b, 4 a, a n d 4 b.  
•  
B N T 1 6 2 b 4 will b e c o m bi n e d wit h B N T 1 6 2 b 2 M o n o v al e nt ( O MI X B B. 1. 5) f or D o s e  2 i n 
C o h ort s  3 a, 3 b, 4 a a n d 4 b.  
•  
B N T 1 6 2 b 4 al o n e will b e gi v e n f or D o s e  1 a n d D o s e  2 i n C o h ort  5.  
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An Internal Review Committee (IRC) will be established and maintained for the entire trial to 
periodically review subject safety data and make decisions about dose escalations (for details 
about the IRC, see Section 10.1.5). 
The staggered dosing process for Cohorts 1 to 4 
The trial will use a staggered dosing process schema with sentinel subjects in Cohorts 1, 2, 3a, 
and 4a (see Figure 1). 
The trial will be initiated with Cohort 1 where eight sentinel subjects will be randomized 3:1 to 
receive one dose of either BNT162b2 Bivalent + BNT162b4 or control BNT162b2 Bivalent followed 
by IRC review of 7 d post-Dose 1 data. 
If the IRC considers the shown tolerability to be acceptable and no stopping/pausing rules are met, 
52 additional trial subjects (expansion group) will be randomized 3:1 to the BNT162b2 Bivalent + 
BNT162b4 or control group BNT162b2 Bivalent (one dose). Following dosing of the expansion 
group (7 d post-Dose 1), all available clinical, laboratory and other relevant data from these 60 trial 
subjects (full cohort) will be reviewed by the IRC. If the IRC considers the shown tolerability is 
acceptable and no stopping/pausing rules are met for Cohort 1, enrollment will be opened for 
Cohort 2. Cohort 2 will follow the same dose escalation/assessment process. For a graphical 
depiction of the staggered dosing process for Cohorts 1 to 4, see Figure 1. 
If the IRC considers the shown tolerability acceptable and no stopping/pausing rules are met for 
Cohort 2 (for the stopping/pausing rules, see Section 7.1), enrollment will be opened for 
Cohorts 3a and 3b which will follow the same dose escalation/assessment process as for 
Cohorts 1 and 2 with the following exception: enrollment for the Cohort 3b will be opened after 7 d 
post-dose data for Cohort 3a sentinel subjects has been reviewed by the IRC and approval is 
granted. There will be a safety review of 7 d post-dose data for the first 8 subjects in Cohort 3b. In 
addition to safety data being reviewed on an ongoing basis by investigators and sponsor, 7 d post-
dose data for Cohort 3a expansion subjects and Cohort 3b subjects will be reviewed by the IRC. 
If the IRC considers the shown tolerability acceptable and no stopping/pausing rules are met for 
Cohorts 3a and 3b (for the stopping/pausing rules, see Section 7.1), enrollment will be opened for 
Cohorts 4a and 4b which will follow the same IRC review process as for Cohorts 3a and 3b. In 
addition to safety data being reviewed on an ongoing basis by investigators and sponsor, 7 d post-
dose data for Cohort 4a expansion subjects and Cohort 4b subjects will be reviewed by the IRC. 
Dose escalation decisions to progress to the next DL and DL modifications (i.e., dropping the DL to 
the previous acceptable DL or to an ‘in-between’ DL) will be confirmed by the IRC. Dose escalation 
will only continue if the safety and tolerability of the previous DL was considered acceptable by the 
IRC and no stopping/pausing rules were met. 
In addition to the above safety reviews for dose modifications, other unplanned dose modifications, 
pausing (temporary halting) of trial treatment, or discontinuation of trial treatment may be required. 
See Section 7.1 for guidance on criteria for such cases. 
For Dose 2 recipients, IRC safety review will be performed for the first 8 subjects 7 d post-Dose 2 
in all DL cohorts (see Table 1). 
Based on the WHO’s recommendation, which has been endorsed by the FDA, and the FDA 
approval of BNT162b2 Monovalent (OMI XBB.1.5), Dose 2 for Cohorts 1 to 4 will be provided in 
line with current agency recommendations when available in the US. This will provide standard of 
care for vaccinees and carries a proven benefit for the current circulating XBB subvariants. 
 

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Figure 1: 
The staggered dosing process for Cohorts 1 to 4 
a. 
Further dosing of subjects or opening of new cohorts will proceed if acceptable tolerability is shown and no stopping/pausing rules are met. 
b. 
Enrollment for Cohort 3b and 4b will be opened after 7 d post-dose data for Cohort 3a and 4a (respectively) sentinel subjects have been reviewed by the IRC and approval for 
progression is granted. 
Abbreviations: d = day(s); IRC = Internal Review Committee; N = number of subjects. 

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1.2 
Schema of the trial (graphical representations of the trial) 
 
 
Figure 3: 
Schema for Cohorts 1 to 4 
Abbreviations: * = sentinel subjects only; AE = adverse event; AESI = adverse event of special interest; COVID-19 = Coronavirus disease 2019; D1, D2 = dose 1, dose 2; 
N = number of subjects; SAE = serious adverse event; yrs = years. 

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Figure 4: 
Schema for Cohort 5 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; COVID-19 = Coronavirus disease 2019; D1, D2 = dose 1, dose 2; N = number of subjects; 
SAE = serious adverse event; yrs = years. 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
Tri al n u m b er: B N T 1 6 2 -2 1  
P a g e 2 2  of 1 1 8  
V er si o n: 8. 0  
D at e: 1 6 S E P 2 0 2 4  
 
 
q . 
I nf or m e d c o n s e nt c a n b e o bt ai n e d f or D o s e 2 at eit h er Vi sit  5, 6 or Vi sit  7.  
r. 
O nl y f or s u bj e ct s t h at r e c ei v e d B N T 1 6 2 b 2 Bi v al e nt + B N T 1 6 2 b 4 f or D o s e 1 a n d w h o c o n s e nt e d t o a s e c o n d ( D o s e  2 ). 
s . 
T o b e c o m pl et e d b ef or e a d mi ni str ati o n of D o s e  2.  
t. 
I n c a s e of a c o m bi n e d Vi sit 6 + 7 all a s s e s s m e nt s/ s a m pli n g s li st e d f or b ot h vi sit s, o nl y n e e d t o b e d o n e o n c e. Bl o o d dr a w f or
a s s e s s m e nt s  m u st b e o bt ai n e d pri or t o D o s e  2 . 
u . 
N ot f or C o h ort s 4 a a n d 4 b.  
v.  
O bt ai n e d l o c all y f or c e ntr al l a b or at or y  t e sti n g. 
 
N ot e s  
T h e t ot al bl o o d v ol u m e dr a w n o v er a n y 8 -w e e k p eri o d i n a n y c o h ort will al w a y s b e l e s s t h a n 5 5 0  m L. A d diti o n al bl o o d s a m pl e s m a y b e t a k e n, e. g., f or s af et y a s s e s s m e nt s aft er A E s or S A E s. 
A s s u mi n g t h er e ar e n o u n pl a n n e d vi sit s, t h e t ot al v ol u m e of bl o o d dr a w n fr o m e a c h s u bj e ct d uri n g tri al p arti ci p ati o n will b e u p t o ~ 1, 8 6 0  m L.  
 
A b br e vi ati o n s : A E = a d v er s e e v e nt;
; C O VI D -1 9  = c or o n a vir u s d i s e a s e 2 0 1 9; d  =  d a y( s); D  =  d o s e; E arl y t er m.  =  e arl y t er mi n ati o n ( vi sit); 
E C G  =  el e ctr o c ar di o gr a m; F U = f oll o w -u p ( vi sit); h  =  h o ur( s); β -H C G = b et a h u m a n c h ori o ni c g o n a d otr o pi n;
 I M P = i n v e sti g ati o n al m e di ci n al pr o d u ct; m = 
m o nt h ( s); N A A T = n u cl ei c a ci d a m plifi c ati o n -b a s e d t e st; N/ A = n ot a p pli c a bl e; S A E = s eri o u s a d v er s e e v e nt; S A R S -C o V -2 = s e v er e a c ut e r e s pir at or y s y n dr o m e c or o n a vir u s  2; 
V O C B P  =  v ol u nt e er s of c hil d b e ari n g p ot e nti al . 
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TABLE OF CONTENTS 
PROTOCOL UPDATE SUMMARY OF CHANGES 
2 
1 
PROTOCOL SUMMARY 
3 
1.1 
Synopsis 
3 
1.2 
Schema of the trial (graphical representations of the trial) 
15 
1.3 
Schedule of activities 
17 
TABLE OF CONTENTS 
23 
LIST OF TABLES 
27 
LIST OF FIGURES 
27 
ABBREVIATIONS/TERMS 
28 
2 
INTRODUCTION 
30 
2.1 
Background 
30 
2.1.1 
The medical need 
30 
2.1.2 
Background to the trial treatments 
30 
2.2 
Trial rationale 
32 
2.3 
Benefit/risk assessment 
34 
2.3.1 
Benefit assessment 
34 
2.3.2 
Risk assessment 
34 
2.3.3 
Overall benefit/risk conclusion 
36 
3 
OBJECTIVES AND ENDPOINTS 
37 
4 
TRIAL DESIGN 
38 
4.1 
Overall design 
38 
4.1.1 
Duration of all trial periods 
40 
4.1.2 
Planned number of trial subjects 
41 
4.2 
Scientific rationale for the trial design 
41 
4.3 
Justification for the trial treatment 
41 
5 
TRIAL POPULATION 
43 
5.1 
Inclusion criteria 
43 
5.1.1 
Inclusion criteria – Cohorts 1 to 4 
43 
5.1.2 
Inclusion criteria – Cohort 5 
46 
5.2 
Exclusion criteria 
46 
5.2.1 
Exclusion criteria – Cohorts 1 to 4 
46 
5.2.2 
Exclusion criteria – Cohort 5 
49 
5.3 
Lifestyle considerations 
49 
5.3.1 
Contraception and donation or cryopreservation of germ cells 
50 
5.4 
Screen failures 
50 

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6 
TRIAL TREATMENTS 
50 
6.1 
Trial treatments administered 
51 
6.2 
Preparation/handling/storage/accountability 
52 
6.3 
Measures to minimize bias: randomization and blinding 
52 
6.3.1 
Allocation of IMP 
52 
6.3.2 
Blinding 
52 
6.4 
Trial treatment compliance 
54 
6.5 
Concomitant therapy 
54 
6.5.1 
Prohibited concomitant therapies during the trial 
54 
6.5.2 
Permitted concomitant therapies during the trial 
55 
6.5.3 
Recording of concomitant therapy during the trial 
55 
6.6 
Dose modifications 
55 
6.7 
Access to trial treatment after the end of the trial 
55 
7 
DISCONTINUATION OF TRIAL TREATMENT AND TRIAL SUBJECT 
DISCONTINUATION/WITHDRAWAL 
56 
7.1 
Discontinuation (stopping) or pausing (temporary halting) of trial treatment 
56 
7.1.1 
Cohort trial treatment pausing rules 
56 
7.1.2 
Individual trial subject trial treatment pausing rules 
57 
7.1.3 
Criteria for temporarily delaying enrollment or randomization 
58 
7.2 
Trial subject discontinuation or withdrawal from the trial 
58 
7.3 
Lost to follow-up 
58 
7.4 
Replacement of permanently discontinued trial subjects 
58 
8 
TRIAL ASSESSMENTS AND PROCEDURES 
59 
8.1 
Efficacy assessments 
59 
8.2 
Safety assessments 
59 
8.2.1 
Physical examinations 
59 
8.2.2 
Vital signs and height and body weight 
60 
8.2.3 
Electrocardiograms 
60 
8.2.4 
Clinical laboratory tests 
61 
8.2.5 
Subject e-diaries for assessment of reactogenicity (local and systemic reactions) 
61 
8.2.6 
Subject e-diaries for assessment of reactogenicity (local and systemic reactions) – Trial 
site personnel and investigator tasks 
63 
8.2.7 
Assessment of local reactogenicity – Investigator tasks 
64 
8.2.8 
COVID-19 surveillance 
64 
8.3 
Adverse events and SAEs 
67 
8.3.1 
Time period and frequency for collecting AE and SAE information 
67 
8.3.2 
Detecting and reporting AEs and SAEs 
67 
8.3.3 
Follow-up of AEs and SAEs 
68 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
Tri al n u m b er: B N T 1 6 2 -2 1  
P a g e 2 5  of 1 1 8  
V er si o n: 8. 0  
D at e: 1 6 S E P 2 0 2 4  
 
 
8. 3. 4  
R e p orti n g r e q uir e m e nt s f or S A E s i n cl u di n g S U S A R s  
6 8  
8. 3. 5  
Pr e g n a n c y t e sti n g a n d h a n dli n g of pr e g n a n ci e s  
6 9  
8. 3. 6  
D e at h e v e nt s  
6 9  
8. 3. 7  
Di s e a s e -r el at e d e v e nt s/ o ut c o m e s n ot q u alif yi n g a s A E s or S A E s 
7 0  
8. 3. 8  
A d v er s e e v e nt s of s p e ci al i nt er e st ( A E SI s)  
7 0  
8. 4  
Pr o c e d ur e s i n c a s e of o v er d o s e or err or s i n I M P a d mi ni str ati o n  
7 1  
8. 5  
P h ar m a c o ki n eti c s  
7 1  
8. 6  
G e n eti c s  
7 1  
8. 7  
I m m u n e r e s p o n s e s 
7 1  
8. 7. 1  
E x pl or at or y r e s e ar c h  
7 2  
8. 8  
C oll e cti o n of d e m o gr a p hi c a n d ot h er b a s eli n e c h ar a ct eri sti c s  
7 3  
8. 9  
U n s c h e d ul e d vi sit( s)  
7 3  
8. 1 0  
E arl y t er mi n ati o n vi sit( s)  
7 3  
9  
S T A TI S TI C A L C O N SI D E R A TI O N S  
7 3  
9. 1  
St ati sti c al h y p ot h e s e s  
7 3  
9. 2  
S a m pl e si z e d et er mi n ati o n  
7 3  
9. 3  
A n al y si s s et s  
7 4  
9. 4  
St ati sti c al a n al y s e s  
7 4  
9. 4. 1  
G e n er al c o n si d er ati o n s  
7 4  
9. 4. 2  
Pri m ar y s af et y e n d p oi nt s  
7 5  
9. 4. 3  
S e c o n d ar y i m m u n o g e ni cit y e n d p oi nt s  
7 5  
9. 4. 5  
Ot h er s af et y a n al y s e s  
7 6  
9. 4. 6  
Ot h er a n al y s e s  
7 6  
9. 5  
I nt eri m a n al y s e s 
7 6  
1 0  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L C O N SI D E R A TI O N S  
7 6  
1 0. 1  
R e g ul at or y, et hi c al, a n d tri al o v er si g ht c o n si d er ati o n s  
7 6  
1 0. 1. 1  
R e g ul at or y a n d et hi c al c o n si d er ati o n s  
7 7  
1 0. 1. 2  
Fi n a n ci al di s cl o s ur e  
7 7  
1 0. 1. 3  
I nf or m e d c o n s e nt pr o c e s s 
7 8  
1 0. 1. 4  
D at a pr ot e cti o n  
7 8  
1 0. 1. 5  
C o m mitt e e s –  I R C 
7 9  
1 0. 1. 6  
Di s s e mi n ati o n of cli ni c al tri al d at a  
7 9  
1 0. 1. 7  
D at a q u alit y a s s ur a n c e  
8 0  
1 0. 1. 8  
S o ur c e d o c u m e nt s  
8 0  
1 0. 1. 9  
P u bli c ati o n p oli c y  
8 1  
1 0. 1. 1 0  
Pr ot o c ol pr e p ar ati o n a n d a p pr o v al  
8 1  
1 0. 1. 1 1  
I n v e sti g at or s a n d tri al a d mi ni str ati v e str u ct ur e 
8 1  
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10.1.12 
Premature termination or suspension of the trial 
83 
10.1.13 
Reporting of serious breaches 
83 
10.2 
Data collection and management 
84 
10.2.1 
Data management 
84 
10.2.2 
Case report forms 
84 
10.2.3 
Subject-reported outcomes 
84 
10.2.4 
Investigator’s Site File and the Trial Master File 
84 
10.3 
Clinical laboratory tests 
85 
10.4 
Adverse events: Definitions and procedures for recording, evaluating, follow-up, and 
reporting 
85 
10.4.1 
Definition of AEs 
85 
10.4.2 
Definition of SAEs 
88 
10.4.3 
Recording and follow-up of AEs and/or SAEs 
89 
10.4.4 
Reporting of SAEs 
93 
10.4.5 
Assessment of laboratory abnormalities 
94 
10.5 
Contraceptive guidance and collection of pregnancy information 
94 
10.5.1 
Definitions 
94 
10.5.2 
Contraception guidance 
95 
10.5.3 
Collection of pregnancy information 
95 
10.6 
Liver safety: Suggested actions and follow-up assessments 
96 
10.7 
Standard definitions 
96 
10.7.1 
Trial site start/closure and trial discontinuation 
96 
10.7.2 
Trial completer and end of trial definitions 
97 
10.8 
Protocol amendments and updates 
97 
10.8.1 
Update from protocol version 1.0 to 2.0 
97 
10.8.2 
Update from protocol version 2.0 to 3.0 
97 
10.8.3 
Update from protocol version 3.0 to 4.0 
98 
10.8.4 
Update from protocol version 4.0 to 5.0 
99 
10.8.5 
Update from protocol version 5.0 to 6.0 
99 
10.8.6 
Update from protocol version 6.0 to 7.0 
100 
11 
REFERENCES 
101 
12 
ADVERSE REACTION MANAGEMENT 
103 
12.1 
Management of local and systemic reactogenicity events 
103 
12.2 
Management of symptoms that could represent myocarditis or pericarditis 
104 
12.3 
Management of risks associated with anemia 
104 
12.4 
Management of risks linked to the pandemic COVID-19 
105 
13 
COHORT 5 SPECIFIC INFORMATION 
105 
13.1 
Summary – Cohort 5 
105 

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13.2 
Introduction – Cohort 5 
105 
13.2.1 
Background 
105 
13.2.2 
Rationale 
105 
13.2.3 
Benefit/risk assessment 
105 
13.3 
Trial design – Cohort 5 
105 
13.3.1 
Planned number of trial subjects 
105 
13.3.2 
Trial duration 
106 
13.4 
Trial assessments and procedures – Cohort 5 
106 
13.5 
Schedule of activities – Cohort 5 
107 
13.6 
Objectives and endpoints – Cohort 5 
112 
13.7 
Trial population – Cohort 5 
113 
13.7.1 
Inclusion criteria – Cohort 5 
113 
13.7.2 
Exclusion criteria – Cohort 5 
115 
13.8 
Trial treatments – Cohort 5 
118 
13.9 
Statistical considerations – Cohort 5 
118 
 
LIST OF TABLES 
Table 1: 
Schedule of IRC and safety reviews 
9 
Table 2: 
Number of trial subjects per trial treatment (total number of subjects enrolled = ~380) 13 
Table 3: 
Schedule of activities – Cohorts 1 to 4 
17 
Table 4: 
Local reaction grading scale 
62 
Table 5: 
Systemic reaction grading scale 
63 
Table 6: 
Probability of observing at least 1 AE, by assumed true event rate 
73 
Table 7: 
Schedule of activities – Cohort 5 
107 
 
LIST OF FIGURES 
Figure 1: 
The staggered dosing process for Cohorts 1 to 4 
10 
Figure 2: 
The dosing process for Cohort 5 
11 
Figure 3: 
Schema for Cohorts 1 to 4 
15 
Figure 4: 
Schema for Cohort 5 
16 
 
 
 

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2 
INTRODUCTION 
2.1 
Background 
2.1.1 
The medical need 
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China. 
In February 2020, the virus was officially named SARS-CoV-2, and the WHO officially 
named the disease caused by SARS-CoV-2 as COVID-19. SARS-CoV-2 infections and 
the resulting disease, COVID-19, have spread globally, and in March 2020, the WHO 
characterized the COVID-19 outbreak as a pandemic. To date, there have been 
>584 million confirmed cases of COVID-19 and >6.4 million have died, demonstrating an 
urgent need for efficacious vaccines (WHO Coronavirus [COVID-19] Dashboard, accessed 
10 AUG 2022). 
Numerous COVID-19 vaccines are currently in development globally, and several 
COVID-19 vaccines (e.g., RNA-based vaccines and adenovirus-vectored vaccines 
expressing the S protein) have been shown to be efficacious in the prevention of 
COVID-19 in clinical trials and are now available under emergency authorizations. For a 
list of such vaccines, see the WHO website “COVID-19 Vaccines with WHO Emergency 
Use Listing” at: (https://extranet.who.int/pqweb/vaccines/vaccinescovid-19-vaccine-eul-
issued). 
Recently a number of new SARS-CoV-2 viral variants has emerged with multiple 
mutations in the S protein. These variants might be associated with the lower efficacy of 
some of the current vaccines. Therefore, there is a need to continue research including 
new approaches to overcome waning immunity and/or the development of modified 
vaccines. 
The SARS-CoV-2 Omicron variant continues its rapid evolution, with significant mutational 
changes noted in late 2022, resulting in a fast changing epidemiological landscape. This 
evolution has given rise to the XBB variants, derived from a recombination between 
Omicron BA.2.75 and BA.2.10.1.4-7 (European Centre for Disease Prevention and Control 
[ECDC] update). 
At present, Omicron and its sublineages continue to cause most SARS-CoV-2 infections. 
Omicron XBB.1 descendent sublineages (i.e., XBB.1.5, XBB.1.16, XBB.1.9, JN.1) that 
predominate in the US and globally are more antigenically distant from prior Omicron 
strain sublineages (e.g., BA.1, BA.5); more so than the distance of these early Omicron 
sublineages from the ancestral Wuhan-Hu-1 strain. They also show the greatest 
magnitude of immune escape that has been observed to date. 
2.1.2 
Background to the trial treatments 
Vaccines targeting the S protein of SARS-CoV-2 have been used as an important 
mitigation strategy of the COVID-19 pandemic. There are currently three vaccines, 
including BNT162b2, that target the S protein authorized or approved for use in the US. 
BNT162b2 includes a nucleoside-modified RNA encapsulated in RNA-LNP, whereby the 
RNA encodes the stabilized trimeric wild type S protein. BNT162b2 has been granted 
emergency use authorization (EUA) for individuals 6 months of age and above 
(Pfizer/BioNTech COVID-19 Vaccine), and has been licensed for individuals 16 yrs of age 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
Tri al n u m b er: B N T 1 6 2 -2 1  
P a g e 3 2  of 1 1 8  
V er si o n: 8. 0  
D at e: 1 6 S E P 2 0 2 4  
 
 
S  pr ot ei n. H o w e v er, t h e r at e of m ut ati o n s i n n o n -s pi k e S A R S -C o V -2  pr ot ei n s i s m u c h 
l o w er t h a n t h e m ut ati o n r at e o b s er v e d i n S  pr ot ei n. E pit o p e s eli citi n g p ot e nt T -c ell 
r e s p o n s e s h a v e b e e n r e p ort e d t o b e l ar g el y v ari a nt-i n d e p e n d e nt (T ar k e et al.  2 0 2 1 b ). A s 
t h e vir u s c o nti n u e s t o a c q uir e m or e m ut ati o n s wit h p ot e nti all y gr e at er i m p a ct o n h u m or al 
a n d c ell ul ar r e s p o n s e s, r ai si n g T -c ell r e s p o n s e s t hr o u g h v a c ci n ati o n a g ai n st b ot h s pi k e 
a n d c o n s er v e d n o n -s pi k e a nti g e n s c o ul d pr o vi d e m or e st a bl e a n d d ur a bl e T  c ell pr ot e cti v e 
i m m u nit y. 
T h e s el e cti o n of e pit o p e s c o n s er v e d a cr o s s S A R S -C o V -2 v ari a nt s t h at ar e pr e di ct e d t o 
bi n d m ulti pl e all el e s , c o m bi n e d  wit h k n o wl e d g e of t h e e pit o p e pr ot ei n e x pr e s si o n , i s k n o w n 
t o b e cr u ci al w h e n d e si g ni n g t h er a p e uti c s pr o vi di n g  l o n g l a sti n g T c ell i m m u nit y 
(P or a n  et  al.  2 0 2 0 ). I n a d diti o n, i n or d er t o f a c e t h e c h all e n g e of p arti al pr ot e cti o n, t h e u s e  
of v a c ci n e s t ar g eti n g a c o m bi n ati o n of B a n d T  c ell e pit o p e s m a y pr o vi d e l o n g  l a sti n g 
i m m u nit y. 
B a s e d o n t hi s r ati o n al e, t hi s tri al will  e v al u at e a  v a c ci n e c a n di d at e , c o m p o s e d  of 
B N T 1 6 2 b 4 a n d B N T 1 6 2 b 2 Bi v al e nt  dr u g pr o d u ct s.  B N T 1 6 2 b 4 i s  a n R N A v a c ci n e 
c o m p o n e nt t ar g eti n g n u cl e o c a p si d, m e m br a n e
 T h e  
m e m br a n e a n d
wit hi n B N T 1 6 2 b 4 h a v e  b e e n l ar g el y c o n s er v e d a cr o s s 
diff er e nt vir al v ari a nt s (i. e. , O mi cr o n) . B N T 1 6 2 b 4 will b e  eit h er mi x e d wit h B N T 1 6 2 b 2  
Bi v al e nt  or B N T 1 6 2 b 2 M o n o v al e nt ( O MI  X B B. 1. 5) dr u g pr o d u ct , a n R N A v a c ci n e  t ar g eti n g 
t h e S A R S -C o V -2  s pi k e pr ot ei n , or gi v e n al o n e . O n 3 1  A U G  2 0 2 2, t h e U S F D A i s s u e d a n 
e m er g e n c y u s e a ut h ori z ati o n ( E U A ) f or a b o o st er v a c ci n ati o n ( 3 0 µ g) wit h t h e B N T 1 6 2 b 2 
B i v al e nt ( B N T 1 6 2 b 2 W T/ O MI B A. 4/B A. 5) f or i n di vi d u al s 1 2  yr s of a g e a n d ol d er.  
D at a s u p p ort i n g cli ni c al i n v e sti g ati o n of B N T 1 6 2 b 4 a n d B N T 1 6 2 b 2  Bi v al e nt  or B N T 1 6 2 b 2 
M o n o v al e nt ( O MI  X B B. 1. 5)  
N o n -cli ni c al st u di e s i n mi c e wit h B N T 1 6 2 b 4 a n d B N T 1 6 2 b 2  c o -a d mi ni str ati o n s h o w e d a 
si mil ar i m m u n o g e ni cit y, a s m e a s ur e d b y n e utr ali z ati o n tit er s i n a p s e u d o vir u s 
n e utr ali z ati o n a s s a y , t o t h at s e e n wit h B N T 1 6 2 b 2 al o n e w h e n mi c e ar e gi v e n a 
pri m e/ b o o st r e gi m e n . I n pr e cli ni c al m o u s e m o d el s, B N T 1 6 2 b 4 h a s b e e n s h o w n t o pr o vi d e 
i n cr e a s e d T-c ell r e s p o n s e s t o t h e a nti g e n c o m p o n e nt s. F or f urt h er d et ail s, s e e  t h e 
B N T 1 6 2 b 4 ( C O VI D -1 9 V a c ci n e) i n v e sti g at or’ s br o c h ur e (I B, B N T 1 6 2 b 4  I B) a n d d at a o n 
fil e. T h e s u p pl e m e nt al bi ol o gi c al li c e n s e a p pli c ati o n f or t h e B N T 1 6 2 b 2 M o n o v al e nt ( O MI 
X B B. 1. 5) v a c ci n e  w a s a p pr o v e d i n t h e U S  o n 1 1  S E P  2 0 2 3 . 
2. 2  
Tri al r ati o n al e  
V a c ci n e s t ar g eti n g t h e s pi k e gl y c o pr ot ei n ( S  pr ot ei n) of S A R S -C o V -2 h a v e b e e n u s e d a s a 
miti g ati o n str at e g y of t h e C O VI D -1 9 p a n d e mi c. B N T 1 6 2 b 2 h a s r e c ei v e d a ut h ori z ati o n f or 
e m er g e n c y s u p pl y, c o n diti o n al m ar k eti n g a ut h ori z ati o n, a n d/ or f ull a ut h ori z ati o n i n m or e 
t h a n 1 0 0 c o u ntri e s gl o b all y u n d er t h e tr a d e n a m e “ C O MI R N A T Y” f or t h e pr e v e nti o n of 
C O VI D -1 9 c a u s e d b y S A R S -C o V -2. B N T 1 6 2 b 2, a N 1 -m et h yl p s e u d o uri di n e -n u cl e o si d e -
m o difi e d R N A e n c o di n g t h e S  pr ot ei n t h at i s e n c a p s ul at e d i n L N P s , h a s d e m o n str at e d 
p ot e nt i m m u n o g e ni cit y, hi g h v a c ci n e effi c a c y, a n d a f a v or a bl e s af et y pr ofil e i n P h a s e  I//II/III 
tri al s, a s w ell a s i n r e al w orl d u s a g e. I n li g ht of t h e i n cr e a s e i n t h e n u m b er of V O C s , a s w ell 
a s t h e n u m b er of n e w m ut ati o n s i n t h e S  pr ot ei n i n t h e s e v ari a nt s, a l o n g t er m a n d d ur a bl e 
i m m u n e r e s p o n s e t ar g eti n g c o n s er v e d vir al e pit o p e s c o ul d h el p pr ot e ct i n di vi d u al s fr o m 
s e v er e s y m pt o m s c a u s e d b y e m er g e nt V O C s.  
C CI
C CI

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
Tri al n u m b er: B N T 1 6 2 -2 1  
P a g e 3 3  of 1 1 8  
V er si o n: 8. 0  
D at e: 1 6 S E P 2 0 2 4  
 
 
T h e v al u e of T -c ell r e s p o n s e s a g ai n st n o n -s pi k e pr ot ei n s h a s b e e n e m p h a si z e d b y t h e ri s e 
of m or e a nti g e ni c all y di v er s e V O C s ( e. g., O mi cr o n s u bli n e a g e s, s u c h a s B A. 1, B A. 2, B A. 4 , 
B A. 5 , a n d X B B), w hi c h c a n a v oi d n e utr ali z ati o n vi a m ut ati o n s t o t h e S pr ot ei n. H o w e v er, 
t h e r at e of m ut ati o n s i n n o n-s pi k e pr ot ei n s i s m u c h l o w er t h a n t h e m ut ati o n r at e o b s er v e d 
i n t h e S pr ot ei n. E pit o p e s eli citi n g p ot e nt T -c ell r e s p o n s e s h a v e b e e n r e p ort e d t o b e l ar g e l y 
v ari a nt -i n d e p e n d e nt. 
B a s e d o n t h e r ati o n al e of t ar g eti n g c o n s er v e d e pit o p e s fr o m m ulti pl e vir al pr ot ei n s t h at 
eli cit p ot e nt T -c ell r e s p o n s e s, Bi o N T e c h i s e v al u ati n g a v a c ci n e c a n di d at e, B N T 1 6 2 b 4, 
ai m e d at e n h a n ci n g t h e br e a dt h of T -c ell r e s p o n s e s a n d t h e pr ot e cti v e c a p a cit y of  s pi k e -
b a s e d v a c ci n e s, e s p e ci all y a g ai n st s e v er e di s e a s e a n d f ut ur e V O C s . 
B N T 1 6 2 b 4 u s e s t h e s a m e m o d R N A pl atf or m, pr o c e s s e s, a n d L N P f or m ul ati o n a s 
B N T 1 6 2 b 2, wit h t h e R N A c o m p o n e nt s c o m pri si n g a si n gl e R N A e n c o di n g s e g m e nt s of t h e 
n u cl e o c a p si d a n d m e m br a n e pr ot ei n s, a s w ell a s s h ort s e g m e nt s c o nt ai ni n g 
. 
I n t hi s tri al, B N T 1 6 2 b 4 will eit h er b e c o m bi n e d wit h t w o s el e ct e d s pi k e -b a s e d R N A 
v a c ci n e s  i. e., B N T 1 6 2 b 2 Bi v al e nt ( W T/ O MI B A. 4/ B A. 5), h er ei n aft er r ef err e d t o a s 
“ B N T 1 6 2 b 2 Bi v al e nt”, a n d B N T 1 6 2 b 2 M o n o v al e nt ( O MI X B B. 1. 5), or gi v e n al o n e. 
•  B N T 1 6 2 b 4 will b e c o m bi n e d wit h B N T 1 6 2 b 2 Bi v al e nt f or D o s e s  1 a n d 2 f or 
C o h ort s  1 a n d 2, a n d D o s e  1 f or C o h ort s  3 a, 3 b, 4 a, a n d 4 b.  
•  B N T 1 6 2 b 4 will b e c o m bi n e d wit h B N T 1 6 2 b 2 M o n o v al e nt ( O MI X B B. 1. 5) f or D o s e  2 
i n C o h ort s 3 a, 3 b, 4 a , a n d 4 b.  
•  B N T 1 6 2 b 4 al o n e will b e gi v e n f or D o s e  1 a n d D o s e  2 i n C o h ort  5.  
B N T 1 6 2 b 2  Bi v al e nt i s a B N T 1 6 2 b 2 -b a s e d v a c ci n e wit h a n R N A e n c o di n g t h e a n c e str al 
str ai n of t h e vir u s S  pr ot ei n i n c o m bi n ati o n wit h a n R N A e n c o di n g t h e S pr ot ei n of t h e 
O mi cr o n B A. 4/ B A. 5 v ari a nt.  B N T 1 6 2 b 2 Bi v al e nt u s e s t h e s a m e m o d R N A pl atf or m, 
pr o c e s s e s, a n d L N P f or m ul ati o n a s li c e n s e d B N T 1 6 2 b 2.  
B N T 1 6 2 b 2 M o n o v al e nt ( O MI X B B. 1. 5) i s a B N T 1 6 2 b 2 -b a s e d v a c ci n e wit h a n R N A 
e n c o di n g t h e S  pr ot ei n of t h e X B B. 1. 5 v ari a nt, a s u b -li n e a g e of O mi cr o n X B B. B N T 1 6 2 b 2 
M o n o v al e nt ( O MI X B B. 1. 5) u s e s t h e s a m e m o d R N A pl atf or m, pr o c e s s e s, a n d L N P 
f or m ul ati o n a s li c e n s e d B N T 1 6 2 b 2. M ar k eti n g a p pr o v al of t h e B N T 1 6 2 b 2 M o n o v al e nt ( O MI 
X B B. 1. 5) v a c ci n e h a s b e e n gr a nt e d . T h e s u p pl e m e nt al bi ol o gi c al li c e n s e a p pli c ati o n f or 
t h e B N T 1 6 2 b 2 M o n o v al e nt ( O MI X B B. 1. 5) v a c ci n e w a s a p pr o v e d i n t h e U S o n 1 1 S E P 
2 0 2 3.  
T h e c o m bi n ati o n of B N T 1 6 2 b 4 a n d B N T 1 6 2 b 2 Bi v al e nt or B N T 1 6 2 b 2 M o n o v al e nt ( O MI  
X B B. 1. 5) i s i nt e n d e d t o i m pr o v e t h e pr ot e cti v e c a p a cit y of s pi k e-b a s e d v a c ci n e s, 
e s p e ci all y a g ai n st s e v er e di s e a s e, t o m a k e t h e pr ot e cti o n l e s s d e p e n d e nt o n vir u s v ari a nt s 
a n d t o h a v e d ur a bl e T  c ell s pr ot e cti v e i m m u nit y. T h e a d diti o n of B N T 1 6 2 b 2 M o n o v al e nt 
( O MI X B B. 1. 5) a d d e d t o B N T 1 6 2 b 4, i s i nt e n d e d t o a d dr e s s t h e m o st r e c e nt 
r e c o m m e n d ati o n s b y W H O a n d e n d or s e d b y t h e U S F D A f or a d diti o n al pr ot e cti o n a g ai n st 
t h e m o st wi d el y cir c ul ati n g v ari a nt li n e a g e X B B. T h e u s e of B N T 1 6 2 b 4 al o n e i s i nt e n d e d t o 
c h ar a ct eri z e t h e i n d u c e d T -c ell i m m u n e r e s p o n s e i n d e p e n d e nt of s pi k e c o -a d mi ni str ati o n.  
F or t h e r ati o n al e f or t h e d o si n g r e gi m e n, s e e S e cti o n  4. 3 . F or t h e r ati o n al e f or t h e 
i m pl e m e nt e d u p d at e s t o t hi s pr ot o c ol, s e e S e cti o n 1 0. 8 . 
C CI
C CI

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2.3 
Benefit/risk assessment 
See the BNT162b4 IB for further information on the expected benefits and risks connected 
with intramuscular (IM) administration of BNT162b4, including the reference safety 
information included in IB Section 6.1.5. 
See the BNT162 IB for further information on the expected benefits and risks connected 
with IM administration of BNT162b2 Bivalent or BNT162b2 Monovalent (OMI XBB.1.5), 
including the reference safety information included in IB Section 7.8.2. 
Clinical investigation of BNT162b4, BNT162b2 Bivalent, and BNT162b2 Monovalent (OMI 
XBB.1.5) is justified given: 
• The threat posed by the antigenically diverse VOCs (e.g., Omicron) emerging 
worldwide. 
• The potential need for enhancing immune responses to overcome waning 
immunity. 
• The potential of the sponsor platform of RNA-based vaccines to deliver high 
numbers of vaccine doses rapidly in a single production campaign. 
2.3.1 
Benefit assessment 
Benefits to individual trial subjects enrolled in this trial may be: 
• Receipt of a further dose of an efficacious and a potentially efficacious COVID-19 
vaccine that may convey a longer duration of protection. 
• Access to COVID-19 diagnostic testing. 
• Contributing to research potentially supporting development of an improved vaccine 
for the prevention of COVID-19 caused by SARS-CoV-2. 
Also, by undergoing the clinical laboratory tests and physical examinations in this trial, 
previously undiagnosed health problems may be uncovered. 
2.3.2 
Risk assessment 
Potential risks related to trial procedures: 
• Trial subjects will be required to attend healthcare facilities during the trial and thus 
there is a potential for increased exposure to SARS-CoV-2. 
• Venipuncture will be performed during the trial. There is the risk of bleeding, 
bruising, hematoma formation, and infection at the venipuncture site. 
• General risks of vaccines and IM injection of vaccines apply here, for details see 
Section 6.2.1 in the BNT162b4 IB. 

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Potential/identified risks of BNT162b4, BNT162b2 Bivalent, and BNT162b2 
Monovalent (OMI XBB.1.5) 
For BNT162b2: 
• Identified risks for BNT162b2 based on clinical and post-authorization data include 
local reactions, such as injection site redness, injection site swelling, and injection 
site pain, and systemic events, such as fever, fatigue, headache, chills, muscle 
pain, and joint pain. 
• Key risks identified for BNT162b2 are myocarditis and pericarditis. 
For BNT162b2 Monovalent (OMI XBB.1.5): 
• BNT162b2 Monovalent (OMI XBB.1.5) has the same modRNA platform (with 
sequence changes that are XBB.1.5 specific) and LNP formulation as BNT162b2; 
therefore, the safety profile is expected to be similar to that of BNT162b2. 
Marketing approval of the BNT162b2 Monovalent (OMI XBB.1.5) vaccine has been 
granted. 
For BNT162b2 Bivalent: 
• BNT162b2 Bivalent has the same modRNA platform and LNP formulations as 
BNT162b2, thus a similar safety profile is expected (for further details of the 
BNT162b2, see the BNT162 IB). 
• A clinical trial to evaluate the safety and tolerability of BNT162b2 Bivalent is 
ongoing (C4591044). This trial is an interventional, randomized, active-controlled, 
Phase II observer-blind investigation of the safety, tolerability, and immunogenicity 
of BNT162b2 Bivalent as a 30 µg booster dose in healthy COVID-19 vaccine 
experienced subjects 12 yrs of age and older. 
For BNT162b4: 
• BNT162b4 has not been studied in humans. This is the first clinical trial to evaluate 
the safety and tolerability of BNT162b4 in combination with BNT162b2 Bivalent or 
BNT162b2 Monovalent (OMI XBB.1.5) or given alone. Since BNT162b4 uses the 
same modRNA platform and LNP formulation as BNT162b2, a similar safety profile 
to BNT162b2 is expected with regards to local and systemic reactogenicities. 
• Myocarditis and pericarditis are considered an important identified risk for 
BNT162b2 vaccines based on post-authorization reports. Based on risks identified 
for other members of the same RNA-based vaccine platform, the risks listed for 
BNT162b2 may apply for BNT162b4. Thus, myocarditis and pericarditis are 
considered a key potential risk for BNT162b4 and are therefore monitored as 
AESIs, see Section 8.3.8. 
• Any potential risks that might be associated with the new non-spike antigens 
encoded by BNT162b4 will be closely monitored throughout the trial. 
• As of 20 Dec 2023, no safety concerns have been identified for the combination of 
BNT162b2 and BNT162b4. Therefore, no new risks or safety concerns are 
expected for BNT162b4 when administered as monotherapy. 

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• Potential risks linked to first-in-human (FIH) administration of BNT162b4 will be 
managed by the planned use of a staggered dosing process with sentinel subjects 
in Cohorts 1, 2, 3a, and 4a. In addition, the trial IRC will assess whether the 
tolerability shown up to 7 d post-dose in the sentinel subjects was acceptable and 
whether any stopping/pausing rules were met. Only when safety and tolerability is 
confirmed by the IRC will dosing of all other subjects per DL cohort be continued. 
The IRC will also assess whether the tolerability shown up to 7 d post-dose in all 
cohort subjects was acceptable and that no stopping/pausing rules were met, 
before allowing progression to the next higher DL cohort. For Cohort 5, an IRC 
safety review of available data for Dose 1 and Dose 2 will be performed after all 
subjects receive Dose 2. For details, including a graphical depiction of the process, 
see Section 1.1. 
For the combination of BNT162b4 and BNT162b2 Bivalent or BNT162b2 Monovalent (OMI 
XBB.1.5): 
• Taking into the account that the total dose of vaccines given in this trial (35, 40, 
45, and 60 µg) is higher than the authorized BNT162b2 dose (30 µg), a higher 
frequency and/or severity of local and systemic reactions cannot be ruled out. 
However, the trial-specific dose escalation process which includes sentinel subjects 
at each DL, usage of e-diaries which allows real time control of entered data and 
defined stopping rules will support appropriate risks minimization measures. 
2.3.3 
Overall benefit/risk conclusion 
Taking into account the measures taken to minimize the risks to subjects in this trial (see 
Section 2.3.2), the potential risks identified in association with administration of the 
investigational BNT162 RNA-based COVID-19 vaccines and the planned trial procedures 
are considered justified by the anticipated benefits that may be afforded to trial subjects. 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
Tri al n u m b er: B N T 1 6 2 -2 1  
P a g e 3 9  of 1 1 8  
V er si o n: 8. 0  
D at e: 1 6 S E P 2 0 2 4  
 
 
B N T 1 6 2 b 4  +  B N T 1 6 2 b 2 M o n o v al e nt ( O MI  X B B. 1. 5) w h e n gi v e n a s D o s e  2 ( b o o st er) i n 
C o h ort s  3 a, 3 b, 4 a, a n d 4 b , a n d 3 0 µ g B N T 1 6 2 b 4 w h e n gi v e n al o n e a s D o s e  1 a n d 
D o s e  2 i n C o h ort  5 . 
F or fl o w di a gr a m s u m m ar i e s of t h e tri al, s e e S e cti o n  1. 2 . F or t h e pl a n n e d a s s e s s m e nt s 
a n d vi sit s, s e e t h e S o A s  i n S e cti o n 1. 3  a n d  S e cti o n  1 3. 5 . 
I n t ot al, u p t o ~3 8 0  h e alt h y s u bj e ct s a g e d 1 8  yr s a n d ol d er will b e e nr oll e d: u p t o 6 0  i n 
e a c h of C o h ort s  1,  2, 3 a, 3 b, 4 a, a n d 4 b  a n d ~ 2 0 i n C o h ort  5 . F or t h e tri al p o p ul ati o n s 
(i n cl u di n g t h e pl a n n e d n u m b er of s u bj e ct s p er c o h ort), d o si n g r e gi m e n s, a n d bli n di n g i n 
C o h ort s  1 t o 5 , s e e T a bl e  2 . 
R a n d o mi z ati o n f or e nr ol l m e nt i n C o h ort s 1, 2, a n d 3 a  will b e str atifi e d b a s e d o n N -bi n di n g 
a nti b o d y st at u s a n d
 
R a n d o mi z ati o n f or e nr oll m e nt i n C o h ort  3 b will b e str atifi e d b a s e d o n a g e a n d N -bi n di n g 
a nti b o d y st at u s. R a n d o mi z ati o n f or e nr oll m e nt i n C o h ort 4 b will b e str atifi e d b a s e d o n a g e  
o nl y. All s u bj e ct s e nr oll e d i n C o h ort s  4 a a n d 4 b , a n d all s u bj e ct s gi vi n g  c o n s e nt f or D o s e  2  
will b e eli gi bl e
 C o h ort s  1 t o 4 ar e o b s er v er -bli n d a n d 
r a n d o mi z e d; C o h ort 5 i s si n gl e ar m a n d o p e n -l a b el. 
T o mi ni mi z e h et er o g e n eit y b et w e e n D L c o h ort s wit h r e g ar d t o t h e b a s eli n e N -bi n di n g 
a nti b o d y st at u s of s u bj e ct s, t h e f oll o wi n g s u bj e ct di stri b uti o n i s pl a n n e d f or e a c h D L c o h ort  
w h e n p o s si bl e : a p pr o xi m at el y 1/ 3 N -bi n di n g a nti b o d y n e g ati v e s u bj e ct s a n d 2/ 3  N -bi n di n g 
a nti b o d y p o siti v e s u bj e ct s i n C o h ort s  1, 2, 3 a, a n d 3 b. H o w e v er, t hi s di stri b uti o n c a n b e 
m o difi e d b a s e d o n t h e e xi sti n g pr e v al e n c e of N -bi n di n g a nti b o d y n e g ati v e s u bj e ct s or 
o p er ati o n al n e e d s.  
S u bj e ct s s cr e e n e d t o t h e s p e cifi c D L c o h ort s , b ut n ot e nr oll e d d u e t o r e a c h e d N -bi n di n g 
s u bj e ct di stri b uti o n r at e , will b e all o w e d t o b e e nr oll e d i nt o t h e n e xt c o h ort. S af et y 
l a b or at or y t e st s ( e x c e pt vir al s cr e e ni n g) will n e e d t o b e r e p e at e d if p erf or m e d > 2 8  d  pri or 
t o t h e pl a n n e d I M P v a c ci n ati o n  d a y . 
I n a d diti o n, d e p e n di n g u p o n t h e o b s er v e d s af et y a n d i m m u n o g e ni cit y d at a, t h e s p o n s or 
m a y u p d at e C o h ort s  1 t o 4  t o e v al u at e hi g h er or a d diti o n al D L s of B N T 1 6 2 b 4 i n 
c o m bi n ati o n wit h t h e s el e ct e d s pi k e -e n c o di n g R N A v a c ci n e B N T 1 6 2 b 2 Bi v al e nt  or 
B N T 1 6 2 b 2 M o n o v al e nt ( O MI  X B B. 1. 5) . 
A n I R C will b e e st a bli s h e d a n d m ai nt ai n e d f or t h e e ntir e tri al t o p eri o di c all y r e vi e w s u bj e ct  
s af et y d at a a n d m a k e d e ci si o n s a b o ut d o s e e s c al ati o n s (f or d et ail s a b o ut t h e I R C, s e e 
S e cti o n  1 0. 1. 5 ). 
T h e st a g g er e d d o si n g pr o c e s s f or C o h ort s  1 t o 4  
T h e tri al will u s e a st a g g er e d d o si n g pr o c e s s s c h e m a wit h s e nti n el s u bj e ct s i n C o h ort s  1, 
2, 3 a , a n d 4 a, s e e Fi g ur e  1 . 
T h e tri al will b e i niti at e d wit h C o h ort  1 w h er e ei g ht s e nti n el s u bj e ct s will b e r a n d o mi z e d 3: 1 
t o r e c ei v e o n e d o s e of eit h er B N T 1 6 2 b 2 Bi v al e nt  +  B N T 1 6 2 b 4 or c o ntr ol B N T 1 6 2 b 2 
Bi v al e nt  f oll o w e d b y I R C r e vi e w of 7 d p o st -D o s e  1 d at a.  
If t h e I R C c o n si d er s t h e s h o w n t ol er a bilit y t o b e a c c e pt a bl e a n d n o st o p pi n g/ p a u si n g r ul e s 
ar e m et, 5 2  a d diti o n al tri al s u bj e ct s  ( e x p a n si o n gr o u p) will b e r a n d o mi z e d 3: 1 t o t h e 
B N T 1 6 2 b 2 Bi v al e nt  +  B N T 1 6 2 b 4 or c o ntr ol gr o u p B N T 1 6 2 b 2 Bi v al e nt  ( o n e d o s e). 
F oll o wi n g d o si n g of t h e e x p a n si o n gr o u p ( 7  d p o st -D o s e  1) , all a v ail a bl e cli ni c al, l a b or at or y 
C CI
C CI

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and other relevant data from these 60 trial subjects (full cohort) will be reviewed by the 
IRC. If the IRC considers the shown tolerability is acceptable and no stopping/pausing 
rules are met for Cohort 1, enrollment will be opened for Cohort 2. Cohort 2 will follow the 
same dose escalation/assessment process. For a graphical depiction of the staggered 
dosing process for Cohorts 1 to 4, see Figure 1. 
If the IRC considers the shown tolerability acceptable and no stopping/pausing rules are 
met for Cohort 2 (for the stopping/pausing rules, see Section 7.1), enrollment will be 
opened for Cohorts 3a and 3b which will follow the same dose escalation/assessment 
process as for Cohorts 1 and 2 with the following exception: enrollment for the Cohort 3b 
will be opened after 7 d post-dose data for Cohort 3a sentinel subjects has been reviewed 
by the IRC and approval is granted. There will be a safety review of 7 d post-dose data for 
the first 8 subjects in Cohort 3b. In addition to safety data being reviewed on an ongoing 
basis by investigators and sponsor, 7 d post-dose data for Cohort 3a expansion subjects 
and Cohort 3b subjects will be reviewed by the IRC. 
If the IRC considers the shown tolerability acceptable and no stopping/pausing rules are 
met for Cohorts 3a and 3b (for the stopping/pausing rules, see Section 7.1), enrollment will 
be opened for Cohorts 4a and 4b which will follow the same IRC review process as for 
Cohorts 3a and 3b. In addition to safety data being reviewed on an ongoing basis by 
investigators and sponsor, 7 d post-dose data for Cohort 4a expansion subjects and 
Cohort 4b subjects will be reviewed by the IRC. 
Dose escalation decisions to progress to the next DL and DL modifications (i.e., dropping 
the DL to the previous acceptable DL or to an ‘in-between’ DL) will be confirmed by the 
IRC. Dose escalation will only continue if the safety and tolerability of the previous DL was 
considered acceptable by the IRC and no stopping/pausing rules were met. 
In addition to the above safety reviews for dose modifications, other unplanned dose 
modifications, pausing (temporary halting) of trial treatment, or discontinuation of trial 
treatment may be required. See Section 7.1 for guidance on criteria for such cases. 
For Dose 2 recipients, IRC safety review will be performed for the first 8 subjects 7 d post-
Dose 2 in all DL cohorts (see Table 1). 
Based on the WHO’s recommendation, which has been endorsed by the FDA, and the 
FDA approval of BNT162b2 Monovalent (OMI XBB.1.5), Dose 2 for Cohorts 1 to 4 will be 
provided in line with current agency recommendations when available in the US. This will 
provide standard of care for vaccinees and carries a proven benefit for the current 
circulating XBB subvariants. 
The dosing process for Cohort 5 
For the dosing process schema for Cohort 5, see Figure 2. Cohort 5 trial subjects will not 
be randomized and will be administered two doses of 30 µg BNT162b4 alone. An IRC 
safety review will be performed after all subjects receive Dose 2 (see Table 1). 
4.1.1 
Duration of all trial periods 
The planned trial duration for each trial subject in Cohorts 1 to 4 who receives only one 
dose of IMP is up to ~7 months (up to ~1 month [28 d] screening and ~6 months follow-up 
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The planned trial duration for each trial subject in Cohorts 1 to 4 who receives two doses 
of IMP is up to ~13 months (up to ~1 month [28 d] screening and ~6 months follow-up after 
Dose 1 of IMP, plus ~6 months follow-up after Dose 1 of IMP). 
See Section 13.3.2 for the planned trial duration for trial subjects in Cohort 5. 
4.1.2 
Planned number of trial subjects 
See Table 2 for the planned number of trial subjects. 
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 
similar published trials for vaccine development following EMA 2017 guidance 
“Strategies to Identify and Mitigate Risks for First-in-Human and Early Clinical Trials with 
Investigational Medicinal Products” and US FDA 2020 guidance “Development and 
Licensure of Vaccines to Prevent COVID-19”. 
No formal sample size calculations have been performed as the trial size is not based on 
any formal hypothesis test. The sample size for each cohort is mainly driven by typical 
small dose escalation designs for early detection of potential safety and reactogenicity 
events. The proposed number of subjects per cohort allows (i) detection of the most 
frequent systemic and local events (AEs and reactogenicity events), thereby allowing dose 
escalation decisions, and (ii) immunogenicity analyses of sufficient scope to support dose 
selection decisions and the trial objectives, while minimizing the number of trial subjects 
exposed to the investigational trial treatment. 
Since the trial treatments are investigational and will be evaluated for the first time in this 
trial, this trial uses a staggered, sequential approach for subject dosing. Dosing will 
proceed with an initial sentinel group of subjects for each DL cohort (Cohorts 1 to 4), and 
for all cohorts pause/stopping rules (see Section 7.1 for details) will be followed, and there 
will be ongoing monitoring by a trial IRC that may pause, permanently discontinue 
administration of trial treatment, or even permanently terminate the trial at any point in 
time. 
Cohorts 3b and Cohort 4b aim to investigate if BNT162b2 Bivalent + BNT162b4 is well 
tolerated and immunogenic in an older population. 
Cohort 5 will evaluate the BNT162b4 component alone to characterize the induced T-cell 
immune response independent of spike co-administration and to inform on potential 
interactions between the components. 
Safety evaluations and vaccine-induced immune responses will be used to assess if there 
is a dose-response, for further details see Section 8.7. 
For the rationale for the implemented updates to this protocol, see Section 10.8. 
4.3 
Justification for the trial treatment 
The proposed starting DL for BNT162b4 in this trial (5 µg) is based on the immunogenicity 
and safety observed in non-clinical studies and on the safety, immunogenicity, and efficacy 
data generated for other members of the same RNA technology platform such as the 
SARS-CoV-2 vaccine BNT162b2 licensed as “COMIRNATY”. BNT162b2 and the 
BNT162b4 and BNT162b2 Bivalent or BNT162b2 Monovalent (OMI XBB.1.5) use the 

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same LNP carrier system, the same nucleoside-modified antigen-encoding RNA, and the 
same untranslated elements of the antigen-encoding RNA (the RNAs differ essentially in 
the encoded ORFs for antigen expression). 
BNT162b2 is authorized for IM administration as a series of two 30 µg IM doses at greater 
than or equal to 21 d (preferably 3 weeks) apart in individuals aged 12 yrs of age or older. 
A booster dose (third dose) of BNT162b2 may be administered ~6 months after the 
second dose in individuals 16 yrs of age and older. 
Since its first marketing authorization in December 2020, BNT162b2 (COMIRNATY) has 
been administered to billions of individuals worldwide. Administration of BNT162b2 in the 
post-authorization setting has confirmed a favorable benefit-risk profile. Pharmacovigilance 
data on BNT162b2 to date continues to support a favorable safety profile. For more 
information about the completed non-clinical studies and the ongoing clinical trials with 
BNT162b2 and the other candidate BNT162b2-based variant vaccines under 
development, see the BNT162 IB. 
The starting dose for BNT162b4 in this trial is lower than what was approved for 
BNT162b2 (5 µg versus 30 µg). The highest BNT162b4 dose planned in this trial (30 µg) is 
the same as that authorized for BNT162b2. The highest cumulative RNA-based vaccine 
dose in this trial will be 60 µg, but the sponsor considers this dose to be acceptable given 
the data listed below which includes good tolerability of cumulative RNA-based vaccine 
doses of up to 60 µg. 
To date, there is very limited clinical experience with vaccine candidates aimed at eliciting 
broader T-cell response against SARS-CoV-2. However, the sponsor considers all 
planned BNT162b4 DLs in this trial (5 µg, 10 µg, 15 µg, and 30 µg) as safe because of: 
• The available non-clinical safety data for the BNT162 vaccine candidates, including 
BNT162b2, support the clinical investigation of the BNT162 vaccine candidates in 
this trial (see the BNT162 IB). This data includes repeat-dose toxicology data for 
doses up to 100 µg in rats. 
• Both vaccine candidates in this trial are derived from the same RNA technology 
platform as the widely used BNT162b2 (COMIRNATY) vaccine that has been 
administered as a series of two 30 µg IM doses to billions of individuals worldwide. 
Administration of BNT162b2 in the post-authorization setting has confirmed a 
favorable benefit-risk profile. 
• The existing clinical data for BNT162b2 has demonstrated that vaccination with 
BNT162b2 as a series of two 30 µg IM doses is safe. 
• Preliminary safety and tolerability data from a 60 µg BNT162b2 booster dose to 
adults 18 yrs of age and older who have received three prior doses of BNT162b2 
(30 µg) at least ≥4 months prior to the booster dose is under investigation in the 
clinical trial C4591031. Based on the currently available data, a 60 µg BNT162b2 
booster dose shows acceptable tolerability. 
• Based on safety data within 7 d post-Dose 4, BNT162b2 Bivalent (BNT162b2 + 
BNT162b2 Omicron BA.4/BA.5) at the 30 µg and 60 µg DLs was generally well 
tolerated across subjects 18 yrs of age and older in the trial C4591044. 

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• The Phase I trial BNT162-01 with DLs of up to 50 µg BNT162b1 (another member 
of the same RNA technology platform where the RNA differs essentially in the 
encoded ORFs for antigen expression) given twice 3 weeks apart, there were no 
SAEs related to the vaccine, while reactogenicity showed clear DL dependency. 
Therefore, the planned BNT162b4, BNT162b2 Bivalent, and BNT162b2 Monovalent (OMI 
XBB.1.5) doses in this trial are considered safe for use in this trial. 
5 
TRIAL POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
Investigators should always use good clinical judgment in considering a volunteer’s overall 
fitness for trial participation. Some volunteers may not be appropriate for enrollment even if 
they meet all inclusion/exclusion criteria. Medical, psychiatric, occupational, or other 
conditions may make evaluation of safety and/or immunogenicity difficult, and some 
volunteers may be poor candidates for retention. 
Determination of eligibility, considering all inclusion and exclusion criteria, must be made 
within 28 d prior to allocation to trial treatment unless otherwise noted in the following 
sections. 
The investigators must maintain documentation supporting compliance with the following 
listed inclusion/exclusion criteria, e.g., interview feedback, outcomes of trial procedures, 
medical records, etc., that confirm volunteers are eligible for inclusion in this trial. 
5.1 
Inclusion criteria 
5.1.1 
Inclusion criteria – Cohorts 1 to 4 
Volunteers are eligible to be included in the trial if all of the following criteria apply: 
1 
Have given informed consent by signing and dating the informed consent form 
(ICF) before initiation of any trial-specific procedures. 
2 
Are willing and able to comply with scheduled visits, treatment schedule, laboratory 
tests, lifestyle restrictions, e.g., to follow good practices to reduce their chances of 
being infected or spreading COVID-19, and other requirements of the trial. This 
includes that they are able to understand and follow trial-related instructions.  
3 
Are aged 18 yrs and older at randomization, have a body mass index over 
18.5 kg/m2 and under 35 kg/m2, and weigh at least 50 kg at Visit 0.  
4 
Are healthy, in the clinical judgment of the investigator based on volunteer-reported 
medical history data, and physical examination, 12-lead electrocardiogram (ECG), 
vital signs, and clinical laboratory test outcomes at Visit 0. 
Note: Healthy volunteers with pre-existing stable disease (e.g., obesity), defined as 
disease not requiring significant change in therapy or hospitalization for worsening 
disease during the 84 d before Visit 0, can be included. 

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5 
Agree not to enroll in another trial with an IMP starting from Visit 0 and until 168 d 
after receiving the last IMP dose. 
Inclusion criteria pertaining to Dose 2: If 168 d after the subject’s first IMP dose had 
passed before they consent to Dose 2, they should agree to not enroll in another 
trial from the time of consent to Dose 2 until 168 d after receiving Dose 2 of the 
IMP. 
6 
Agree not to be vaccinated with: 
• Non-trial vaccines (except COVID-19 vaccines, as per next sub-bullet) 
starting 28 d prior to the Dose 1 and until 28 d after receiving of the last IMP 
dose. Seasonal influenza vaccine is allowed; however, it should be given at 
least 14 d before or after any administration of IMP. 
Inclusion criteria pertaining to Dose 2: If 28 d after the subject’s first IMP 
dose had passed before they consent to continue Dose 2, they should not 
have been vaccinated with non-trial vaccines starting from the time of 
consent to Dose 2 and until 168 d after receiving the Dose 2 of the IMP. 
• Non-trial COVID-19 vaccines starting at least 90 d prior to the Visit 1 and 
until completion of the subject’s last trial visit. 
7 
Have been vaccinated with at least three doses of an RNA-based COVID-19 
vaccine authorized in the US before Visit 0. The last COVID-19 RNA vaccine dose 
must have been administered at least 90 d before Visit 1. 
Note: Documented confirmation of prior COVID-19 vaccine receipt must be 
obtained prior to randomization. 
Virology 
8 
Have negative human immunodeficiency virus (HIV)-1 and HIV-2 test results at 
Visit 0. 
9 
Have negative Hepatitis B surface antigen (HBsAg) test results at Visit 0. 
10 
Have negative anti-Hepatitis C virus (HCV) antibodies, or negative HCV 
polymerase chain reaction (PCR) test results if the anti-HCV is positive at Visit 0. 
Reproductive status and contraception 
11 
Volunteers of childbearing potential (VOCBP) that have a negative serum β-HCG 
pregnancy test result at Visit 0 and negative urine pregnancy test results prior to 
receiving Dose 1. Volunteers born female that are postmenopausal or permanently 
sterilized (verified by medical records) will not be considered VOCBP (for 
definitions of postmenopausal or permanently sterilized, see Section 10.5). 
Inclusion criteria pertaining to Dose 2: VOCBP that have a negative urine 
pregnancy test results prior to receiving Dose 2. 

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12 
VOCBP who agree to practice a highly effective form of contraception (for guidance 
on contraception, see Section 10.5) and to require their male sexual partners to 
use condoms with a spermicidal agent, starting at Visit 0 and continuously until 
28 d after receiving the last IMP dose. 
Inclusion criteria pertaining to Dose 2: If 28 d after the subject’s first IMP dose had 
passed before they consent to continue Dose 2, they should have a negative urine 
β-HCG pregnancy test result at Visit 7 and agree to practice a highly effective form 
of contraception and to require their male sexual partners to use condoms with a 
spermicidal agent, starting from the time they consent to Dose 2 and continuously 
until 28 d after receiving Dose 2 of IMP. 
13 
VOCBP who agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during trial, starting at Visit 0 and continuously until 28 d after 
receiving the last IMP dose. 
Inclusion criteria pertaining to Dose 2: If 28 d after the subject’s first IMP dose had 
passed before they consent to continue Dose 2, they should agree not to donate 
eggs (ova, oocytes) for the purposes of assisted reproduction during trial, starting 
from the time they consent to Dose 2 and continuously until 28 d after receiving 
Dose 2 of IMP. 
14 
Men who are sexually active with partners of childbearing potential and who have 
not had a verified vasectomy (documented in medical records) that agree to use 
condoms with a spermicidal agent and to practice a highly effective form of 
contraception with their sexual partners born female (for guidance on 
contraception, see Section 10.5) starting at Visit 0 and continuously until 28 d after 
receiving the last IMP dose. 
Inclusion criteria pertaining to Dose 2: If 28 d after the subject’s first IMP dose had 
passed before they consent to continue Dose 2, they should agree to use condoms 
with a spermicidal agent and to practice a highly effective form of contraception 
with their sexual partners born female starting from the time they consent to Dose 2 
and continuously until 28 d after receiving Dose 2 of IMP. 
15 
Men who are willing to refrain from sperm donation, starting at Visit 0 and 
continuously until 28 d after receiving the last IMP dose. 
Inclusion criteria pertaining to Dose 2: If 28 d after the subject’s first IMP dose had 
passed before they consent to continue Dose 2, they should agree to refrain from 
sperm donation, starting from the time they consent to Dose 2 and continuously 
until 28 d after receiving Dose 2 of IMP. 
5.1.1.1 
Inclusion criteria (Dose 2 groups) – Cohorts 1 to 4 
Volunteers are eligible to receive Dose 2 of BNT162b4 + BNT162b2 Bivalent or BNT162b4 
+ Monovalent (OMI XBB.1.5) and complete Visits 7 to 11 if all of the following criteria (in 
addition to inclusion criteria 1 to 15) apply: 
16 
Have given informed consent by signing and dating the ICF reflecting protocol 
version 5.0 before administration of Dose 2. 

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17 
Have enrolled in a dose cohort and received Dose 1 of BNT162b4 + BNT162b2 
Bivalent in this trial. 
18 
Are healthy in the opinion of the investigator based on a brief (symptom-directed) 
physical examination as described in Section 8.2.1. 
 
5.1.2 
Inclusion criteria – Cohort 5 
For the inclusion criteria for Cohort 5, see Section 13.7.1. 
5.2 
Exclusion criteria 
5.2.1 
Exclusion criteria – Cohorts 1 to 4 
Volunteers are not eligible to be included in the trial if any of the following criteria apply: 
1 
Breastfeeding or intending to become pregnant starting with Visit 0 until 28 d after 
receiving the last dose of trial IMP or intending to father children starting with Visit 0 
until 28 d after receiving the last trial IMP dose. 
2 
History of any severe adverse reactions to vaccines or to vaccine components and 
including history of anaphylaxis and related symptoms such as hives, respiratory 
difficulty, angioedema, and/or abdominal pain. (Not excluded from participation: a 
volunteer who had an anaphylactic adverse reaction to pertussis vaccine as a 
child). 
3 
Current or history of the following medical conditions: 
a) Uncontrolled or moderate or severe respiratory diseases (e.g., asthma, 
chronic obstructive pulmonary disease); symptoms of asthma severity as 
defined in the most recent US National Heart, Lung, and Blood Institute 
asthma management guidelines - e.g., exclude a volunteer who: 
o Uses a short-acting rescue inhaler (typically a beta 2 agonist) 
daily, or 
o Uses high dose inhaled corticosteroids (per National Heart, Lung, 
and Blood Institute asthma management guidelines [Tables 4–
8b]), or 
o In the past year has either of the following: 
▪ Greater than one exacerbation of symptoms treated with 
oral/parenteral corticosteroids; 
▪ Needed emergency care, urgent care, hospitalization, or 
intubation for asthma. 
b) Diabetes mellitus type 1 or type 2, or new onset of Diabetes mellitus 
type 1 or 2 from the administration of Dose 1, including cases controlled 
with diet alone (Not excluded: history of isolated gestational diabetes). 
c) Hypertension: 

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▪ 
If a person has been found to have elevated blood pressure or 
hypertension during screening or previously, exclude for “blood 
pressure that is not well controlled”. Well controlled blood pressure is 
defined as consistently ≤140 mm Hg systolic and ≤90 mm Hg 
diastolic, with or without medication, with only isolated, brief 
instances of higher readings, which must be ≤150 mm Hg systolic 
and ≤90 mm Hg diastolic at Visit 0. 
▪ 
If a person does not have a history of elevated blood pressure or 
hypertension previously or during screening, also exclude for systolic 
blood pressure ≥150 mm Hg at Visit 0 or diastolic blood pressure 
≥100 mm Hg at Visit 0. 
Exclusion pertaining to Dose 2: Subjects who have new onset of 
worsening hypertension since enrollment, that, in the opinion of the 
investigator would constitute an increased risk to the subject’s 
participation in Dose 2. 
d) Any current or history of cardiovascular diseases such as myocarditis, 
pericarditis, myocardial infarction, symptomatic congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias. 
Exclusion pertaining to Dose 2: Subjects who have new onset of 
cardiovascular disease since enrollment, that, in the opinion of the 
investigator would constitute an increased risk to the subject’s 
participation in Dose 2. 
e) A diagnosed bleeding disorder (e.g., factor deficiency, coagulopathy, or 
platelet disorder requiring special precautions). 
Exclusion pertaining to Dose 2: Subjects who have new onset of a 
bleeding disorder since enrollment, that, in the opinion of the 
investigator, would constitute an increased risk to the subject’s 
participation in Dose 2. 
f) Seizure disorders: History of seizure(s) within the past 3 yrs. Also 
exclude if volunteer has used medications in order to prevent or treat 
seizure(s) at any time within the past 3 yrs. 
g) Screening 12-lead ECG that is consistent with probable or possible 
myocarditis or pericarditis, or demonstrates clinically relevant 
abnormalities that may affect subject safety or interpretation of the trial 
results. 
Exclusion pertaining to Dose 2: Only symptomatic subjects or whose 
clinical picture, in the opinion of the investigator, warrant ECG will have a 
repeat 12-lead ECG prior to Dose 2. 
Note for exclusion criteria 3g: ECG changes including but not limited to: 
paroxysmal or sustained atrial or ventricular arrhythmias, atrioventricular 
(AV) block (grade 2-3) or bundle branch block, diffuse ST-segment 
elevation or PR-segment inversion, QTcF interval (QT interval corrected 
by the Fridericia formula) >450 ms in men and >460 ms in women, 
changes supporting myocardial infarction and/or myocardial ischemia. 

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Exclusion pertaining to Dose 2: Subjects who have an ECG prior to 
Dose 2 and have a change or new onset that, in the opinion of the 
investigator, should not receive Dose 2.  
4 
Current or history of major psychiatric illness, including but not limited to bipolar 
disorder, major depressive disorder, schizophrenia, autism, and attention deficit-
hyperactivity disorder that could interfere with participation and follow-up as 
required by the trial protocol. 
Exclusion pertaining to Dose 2: Subjects who have a change or new onset 
psychiatric illness. 
5 
Current or history of the following diseases associated with immune dysregulation: 
• Primary immunodeficiencies. 
• History of solid organ or bone marrow transplantation. 
• Asplenia: any condition resulting in the absence of a functional spleen. 
• Currently existing or history of autoimmune disease including and not 
limited to thyroid autoimmune disease, multiple sclerosis, or psoriasis. 
Exclusion pertaining to Dose 2: Subjects who have a change or new onset 
immunodeficiency. 
Prior/concomitant therapy 
6 
Received any non-trial IMP within 28 d before Visit 0 or Visit 7. 
7 
Received or planned treatment throughout the entire trial with radiotherapy or 
immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids 
(if systemic corticosteroids are administered for ≥14 d at a dose of ≥20 mg/d of 
prednisone or equivalent), e.g., for cancer or an autoimmune disease, or planned 
receipt throughout this trial. Inhaled/nebulized (except high doses as per exclusion 
criteria 3a), intraarticular, intrabursal, or topical (skin or eyes) corticosteroids are 
permitted. 
8 
Blood/plasma products and/or immunoglobulin containing therapy (including 
monoclonal antibodies) received within 120 d before Visit 1 or Visit 7 or 
administration is planned starting at Visit 0 or prior to Visit 7 until 120 d after the 
last IMP administration in this trial. 
Exclusion pertaining to Dose 2: if 28 d after the subject’s last IMP dose had passed 
before they consent to continue Dose 2, blood/plasma products and/or 
immunoglobulin containing therapy (including monoclonal antibodies) received 
within 120 d before Dose 2 of IMP (Visit 7) continuously until 120 d after receiving 
Dose 2 of IMP. 
9 
Received allergy treatment with antigen injections within 28 d before Visit 1 or 
Visit 7 or where allergy treatment with antigen injections are scheduled within 14 d 
after any visit with IMP administration in this trial. 

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10 
Subjects with a history of SARS-CoV-2 infection (symptomatic or asymptomatic) 
<60 d prior to randomization. 
11 
Have received any non-RNA or unauthorized COVID-19 vaccine, aside from 
Dose 1 of the current trial.  
Additional exclusions 
12 
Any existing condition which may affect IMP administration and/or assessment of 
local reactions assessment at the injection site, e.g., tattoos, severe scars, etc. 
13 
Are vulnerable individuals as per ICH E6 definition, i.e., are individuals whose 
willingness to volunteer in a clinical trial may be unduly influenced by the 
expectation, whether justified or not, of benefits associated with participation, or of 
a retaliatory response from senior members of a hierarchy in case of refusal to 
participate. 
14 
Any screening hematology and/or blood chemistry laboratory value that meets the 
definition of a Grade ≥1 abnormality at Visit 0, or an abnormal C-reactive protein 
(identified by any method) or troponin I value. 
Note: Volunteers with any stable Grade 1 abnormalities (according to the toxicity 
grading scale) may be considered eligible at the discretion of the investigator. 
(Note: “stable” Grade 1 laboratory abnormality is defined as a report of Grade 1 on 
an initial blood sample that remains ≤ Grade 1 upon repeat testing on a second 
sample from the same volunteer). 
Gilberts disease, in and of itself, is not considered exclusionary. 
Exclusion pertaining to Dose 2: Only symptomatic subjects or whose clinical 
picture, in the opinion of the investigator, warrant laboratory investigation, will have 
a repeat lab(s) prior to Dose 2. 
15 
History of alcohol abuse or drug addiction within 1 yr before Visit 0, or a history 
(within the past 5 yrs) of substance abuse or known medical, psychological, or 
social conditions which, in the opinion of the investigator, could compromise their 
wellbeing if they participate as subjects in the trial, or that could prevent, limit, or 
confound the protocol-specified assessments. 
5.2.2 
Exclusion criteria – Cohort 5 
For the exclusion criteria for Cohort 5, see Section 13.7.2. 
5.3 
Lifestyle considerations 
The trial subjects will be required to remain at the site for ~1 hour (h) after each 
administration of trial treatment. When at the trial site, trial subjects will be asked to drink 
fluids (e.g., water) per trial site standard for visits with blood draws. 
Trial subjects will be asked to avoid strenuous exercise beyond their usual exercise routine 
for 6 d after each IMP administration after leaving the trial site. 

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Trial subjects will be required to follow guidance from the trial site personnel on 
recommended social behaviors to avoid SARS-CoV-2 infection (e.g., mask wearing, social 
distancing) and to practice the prescribed forms of contraception (see Sections 5.3.1). 
Trial subjects will be advised to avoid donating blood or blood products during their 
participation in this trial. 
5.3.1 
Contraception and donation or cryopreservation of germ cells 
Currently, the risk of human teratogenicity/fetotoxicity can NOT be excluded by available 
data. Therefore, all male and female trial subjects who, in the opinion of the investigator, 
are biologically capable of having children must agree to use of a highly effective method 
of contraception consistently (see Section 10.5.2) and correctly (as specified in the SoAs, 
see Section 1.3 and Section 13.5). In addition, pregnancy testing will be performed at 
screening and before each IMP administration. 
When obtaining informed consent, the investigator or medically qualified designee will 
inform the trial subject of the need to use highly effective contraception consistently and 
correctly, and will document the conversation. This will include advice about donation and 
cryopreservation of germ cells. In addition, the investigator or designee will instruct the trial 
subject to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected in the trial subject or partner. 
The investigator or his or her designee, in consultation with the trial subject, will confirm 
that the trial subject has selected an appropriate method of contraception for the individual 
trial subject and his or her partner(s) from the permitted list of contraception methods and 
will confirm that the trial subject has been instructed in its consistent and correct use. 
VOCBP will only be administered trial treatment after negative pregnancy test outcome(s) 
at the timepoints indicated in the SoAs (Section 1.3 and Section 13.5). 
For definitions of VOCBP, postmenopausal female and fertile men, as well as guidance on 
how to collect pregnancy information, see Section 10.5. 
5.4 
Screen failures 
Screen failures are defined as individuals who consent to participate in the trial, but did not 
meet one or more eligibility criteria, and therefore were not eligible for randomization 
(allocated to IMP). 
A minimal set of screen failure information is required to ensure transparent reporting of 
screening failures to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, date the ICF was signed, the reasons for screen 
failures, and any SAEs, if applicable. 
If agreed with the trial Medical Monitor, rescreening is allowed at the discretion of the 
investigators. Rescreened subjects will need to re-consent and will be assigned a new trial 
subject number. 
6 
TRIAL TREATMENTS 
Trial treatment is defined as any investigational treatment intended to be administered to a 
trial subject according to the trial protocol. An “IMP” is any medicinal product which is 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
Tri al n u m b er: B N T 1 6 2 -2 1  
P a g e 5 2  of 1 1 8  
V er si o n: 8. 0  
D at e: 1 6 S E P 2 0 2 4  
 
 
6. 2  
Pr e p ar ati o n/ h a n dli n g/ st or a g e/ a c c o u nt a bilit y  
T h e i n v e sti g at or or d e si g n e e m u st c o nfir m a p pr o pri at e t e m p er at ur e c o n diti o n s h a v e b e e n 
m ai nt ai n e d d uri n g tr a n sit f or all tri al tr e at m e nt r e c ei v e d a n d a n y di s cr e p a n ci e s ar e r e p ort e d 
a n d r e s ol v e d b ef or e u s e of t h e tri al tr e at m e nt.  
O nl y tri al s u bj e ct s e nr oll e d i n t h e tri al m a y r e c ei v e tri al tr e at m e nt a n d o nl y a ut h ori z e d sit e 
p er s o n n el m a y s u p pl y or a d mi ni st er tri al tr e at m e nt. All tri al tr e at m e nt m u st b e st or e d i n a 
s e c ur e, e n vir o n m e nt all y c o ntr oll e d, a n d m o nit or e d ( m a n u al or a ut o m at e d) ar e a i n 
a c c or d a n c e wit h t h e l a b el e d st or a g e c o n diti o n s wit h a c c e s s li mit e d t o a ut h ori z e d sit e 
p er s o n n el.  
T h e i n v e sti g at or  i s a c c o u nt a bl e f or tri al tr e at m e nt a c c o u nt a bilit y, r e c o n cili ati o n, a n d r e c or d 
m ai nt e n a n c e (i. e., r e c ei pt, r e c o n cili ati o n, a n d fi n al di s p o siti o n r e c or d s).  
A n y n o n -c o m pli a n c e wit h t h e pr o vi d e d st or a g e c o n diti o n s s h o ul d b e r e p ort e d t o t h e 
s p o n s or u p o n di s c o v er y al o n g wit h a n y a cti o n s t a k e n. O n c e n o n -c o m pli a n c e i s i d e ntifi e d, 
t h e tri al tr e at m e nt m u st b e q u ar a nti n e d a n d n ot u s e d u ntil t h e s p o n s or pr o vi d e s p er mi ssi o n 
t o u s e/ di s c ar d/r et ur n t h e tri al tr e at m e nt. 
F urt h er g ui d a n c e a n d i nf or m ati o n f or t h e st or a g e, h a n dli n g, a n d fi n al di s p o siti o n of tri al 
tr e at m e nt will b e  pr o vi d e d i n t h e P h ar m a c y M a n u al.  
6. 3  
M e a s ur e s t o mi ni mi z e bi a s: r a n d o mi z ati o n a n d bli n di n g  
C o h ort s 1, 2, 3 a, 3 b , 4 a, a n d 4 b ar e o b s er v e r-bli n d f or D o s e  1, t hr o u g h Vi sit  5 o nl y.  Si n c e 
o nl y pri or r e ci pi e nt s of B N T 1 6 2 b 4 will r e c ei v e D o s e  2, D o s e  2 will b e o p e n -l a b el. Tri al 
s u bj e ct s  will b e p er mitt e d t o b e u n bli n d e d fr o m Vi sit  5 . 
C o h ort  5  i s si n gl e ar m a n d o p e n -l a b el f or D o s e 1 a n d D o s e  2.  
6. 3. 1  
All o c ati o n of I M P  
Tr e at m e nt all o c ati o n  will b e d o n e u si n g a n o nli n e r a n d o mi z ati o n t o ol  f or C o h ort s 1 t o 4 , 
a n d o nli n e o p e n -l a b el kit all o c ati o n will b e u s e d f or Co h ort  5 . 
R a n d o mi z ati o n f or e nr ol l m e nt i n C o h ort s 1, 2, a n d 3 a will b e str atifi e d b a s e d o n N -bi n di n g 
a nti b o d y st at u s a n d
 
R a n d o mi z ati o n f or e nr oll m e nt i n C o h ort  3 b will b e str atifi e d b a s e d o n a g e a n d N -bi n di n g 
a nti b o d y st at u s. R a n d o mi z ati o n f or e nr oll m e nt i n C o h ort 4 b will b e str atifi e d b a s e d o n a g e 
o nl y. All s u bj e ct s e nr oll e d i n C o h ort s  4 a a n d 4 b, a n d all s u bj e ct s gi vi n g c o n s e nt f or D o s e  2 
will b e eli gi bl e
 
F or C o h ort s  3 b a n d 4 b, t h e a g e gr o u p di stri b uti o n e nr oll e d will b e ~ 6 0 % of s u bj e ct s a g e d 
≥6 5  yr s a n d ~ 4 0 % of s u bj e ct s a g e d > 5 5 t o < 6 5  yr s.  
All s u bj e ct s i n C o h ort  5 will b e all o c at e d t o a si n gl e ar m.  
6. 3. 2  
Bli n di n g  
F or C o h ort s  1 t o 4, t hi s i s a n o b s er v er -bli n d tri al u ntil  Vi sit  5  ( or l at er, if s u bj e ct s o nl y 
c o n s e nt t o D o s e  2 l at er) . I n di vi d u al s will  b e u n bli n d e d a s d e s cri b e d i n t h e S o A  i n 
S e cti o n  1. 3 . F urt h er d et ail s r el e v a nt t o bli n di n g/ u n bli n di n g pr o c e d ur e s will b e pr o vi d e d i n 
t h e Bli n d  M a n a g e m e nt  Pl a n . 
C o h ort  5 i s o p e n -l a b el. 
C CI
C CI

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6.3.2.1 
Blinding of trial subjects 
All trial subjects in Cohorts 1 to 4 will be blinded to their assigned trial treatments as 
described in the SoA in Section 1.3. 
6.3.2.2 
Blinding of trial site personnel 
The trial staff dispensing and administering the vaccine will be unblinded, but all other trial 
personnel, including the principal investigator, will be blinded as described in the SoA in 
Section 1.3. The principal investigator will assign the responsibility of unblinded dispenser 
and unblinded administrator to persons who will not participate in the evaluation of any trial 
subject. More than one unblinded dispenser/administrator may be assigned. A member of 
the trial site personnel or clinic pharmacy should fulfill this role. Contact between the 
unblinded dispenser/administrator and trial subjects should be kept to a minimum. 
The investigator, trial coordinator, and any site staff other than the unblinded 
dispenser/administrator must not be allowed to know the investigational product assigned 
to any trial subject and must not be allowed to see the investigational product containers. 
BNT162b4 and BNT162b2 Bivalent do not differ in physical appearance but the trial 
treatments differ slightly in volume (and thus could lead to unblinding, e.g., when 
administering the IMP or recording the administered IMP volume), details of the trial 
treatment blinding measures will be provided in the Blind Management Plan. 
The trial may be unblinded to site personnel at timepoints as decided by the sponsor. 
6.3.2.2.1 
Unblinding of trial subjects 
In case of an emergency, the investigator has the sole responsibility for determining if 
unblinding of a trial subject’s trial treatment assignment is warranted. Trial subject safety 
must always be the first consideration in making such a determination. Prior to the trial 
start, the investigator will be provided with guidance relevant to the emergency unblinding 
procedure. 
If the investigator decides that unblinding is warranted to ensure the safety of a trial 
subject, the investigator should make every effort to contact the sponsor prior to unblinding 
the trial subject’s trial treatment assignment unless this could delay further management of 
the trial subject. 
If a subject’s trial treatment assignment is unblinded, the sponsor must be notified within 
24 h after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and case report form (CRF). 
6.3.2.3 
Blinding of laboratory personnel 
In this trial, the laboratory personnel at internal or external laboratories may be unblinded 
to support rolling snapshot analyses. For further details relevant to the unblinding of these 
laboratory personnel, see the Blind Management Plan. 
6.3.2.4 
Blinding of IRC members 
To enable the IRC to provide real time medical oversight of trial subject safety during the 
conduct of this trial, the IRC members will include unblinded sponsor staff. For further 
details about the IRC, see Section 10.1.5. 

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6.3.2.5 
Blinding of sponsor personnel 
Relevant sponsor personnel will be unblinded to trial treatment allocation for the subjects. 
However, sponsor personnel who routinely have contact with blinded site personnel and 
the functions responsible for the daily CRO oversight will be blinded. Further details, see 
the Blind Management Plan. 
6.4 
Trial treatment compliance 
Trial subjects will receive trial treatment directly from the (unblinded) investigator or a 
designee under medical supervision. The date and time of each dose administered must 
be recorded in the source documents and in the CRF. The dose of trial treatment and 
subject identification number will be confirmed at the time of dosing by a member of the 
trial site personnel other than the person administering the trial treatment. 
See Section 8.4 for guidance on the treatment of overdose or errors in drug administration. 
6.5 
Concomitant therapy 
6.5.1 
Prohibited concomitant therapies during the trial 
(See #6 in the inclusion criteria for Cohorts 1 to 4 and #6 in the inclusion criteria for 
Cohort 5) Trial subjects should not have been vaccinated with: 
• Non-trial vaccines (except COVID-19 vaccines) starting 28 d prior to Dose 1 and 
until 28 d after receiving of the last IMP dose (Dose 2). Seasonal influenza vaccine 
is allowed, however it should be given at least 14 d before or after any 
administration of IMP. 
• Non-trial COVID-19 vaccines until 6 months (168 d) post last IMP dose for 
Cohorts 1 to 4 and until 28 d post last IMP dose for Cohort 5.  
Subjects in Cohorts 1 to 4 that continue to Dose 2 should not have been vaccinated 
with non-trial COVID-19 vaccines, starting at least 90 d prior to Visit 1 and until 
completion of the subject’s last trial visit. 
(See #7 in the exclusion criteria for Cohorts 1 to 4 and #7 in the exclusion criteria for 
Cohort 5) Throughout the entire trial, trial subjects should not receive radiotherapy or 
immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids (if 
systemic corticosteroids are administered for ≥14 d at a dose of ≥20 mg/d of prednisone or 
equivalent), e.g., for cancer or an autoimmune disease, or planned receipt throughout this 
trial. Inhaled/nebulized (except high doses as per #3a in the exclusion criteria for 
Cohorts 1 to 4 and #3a in the exclusion criteria for Cohort 5), intraarticular, intrabursal, or 
topical (skin or eyes) corticosteroids are permitted. 
(See #8 in the exclusion criteria for Cohorts 1 to 4 and #8 in the exclusion criteria for 
Cohort 5) Trial subjects should not receive any blood/plasma products and/or 
immunoglobulin containing therapy (including monoclonal antibodies) from Visit 0 or prior 
to Dose 2 until 120 d after the last IMP administration for Cohorts 1 to 4, or until 90 d after 
the last IMP administration for Cohort 5. 
(See #9 in the exclusion criteria for Cohorts 1 to 4 and #9 in the exclusion criteria for 
Cohort 5) Trial subjects should not receive allergy treatment within 14 d after any visit with 
IMP administration in this trial. 

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6.5.2 
Permitted concomitant therapies during the trial 
Seasonal influenza vaccine is allowed; however, it should be given at least 14 d before or 
after any administration of trial IMP. 
The use of antipyretics and other pain medication to treat symptoms after IMP 
administration or for ongoing conditions is permitted, but not to prevent symptoms 
associated with IMP administration (i.e., up to 12 h before each IMP administration). 
Administration of standard therapeutic dose of acetaminophen (preferable), or a 
non-steroidal anti-inflammatory drug (NSAID) if acetaminophen is contraindicated is 
permitted (paracetamol / acetaminophen at doses of up to 4 g/d). 
Inhaled, topical, or localized injections of corticosteroids (e.g., intraarticular or intrabursal 
administration) are permitted. 
Other concomitant medication may be considered on a case-by-case basis by the 
investigator, if considered necessary after consultation with the trial Medical Monitor. 
6.5.3 
Recording of concomitant therapy during the trial 
All concomitant medications used (permitted or prohibited, including over the counter or 
prescription medicines, vitamins, and/or herbal supplements) during the periods defined in 
the SoAs (Section 1.3 and Section 13.5) must be recorded in the CRF along with: 
• The reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The trial Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior medication. 
6.6 
Dose modifications 
The trial design follows a structured dose escalation schema. For details, see Section 4.1. 
Dose escalation decisions to the next DL and DL modifications (i.e., dropping the DL to the 
previous acceptable DL or to an ‘in-between’ DL) will be confirmed by the IRC. 
Cohort DL escalations: dose escalation will only continue if the safety and tolerability of the 
previous DL was considered acceptable by the IRC and no stopping/pausing rules were 
met. 
Other unplanned dose modifications, pausing (temporary halting) of trial treatment, or even 
discontinuation of trial treatment may be required. See Section 7.1 for guidance on criteria 
for such cases. 
6.7 
Access to trial treatment after the end of the trial 
Provision of access to trial treatment after the end of the trial is not planned. 

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7 
DISCONTINUATION OF TRIAL TREATMENT AND TRIAL SUBJECT 
DISCONTINUATION/WITHDRAWAL 
Any safety concerns of the investigators should be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the trial subject should 
continue or discontinue trial treatment. 
7.1 
Discontinuation (stopping) or pausing (temporary halting) of trial 
treatment 
The following pausing rules are established within the trial based on reported AEs, e-diary 
reactogenicity data, ECG findings, and clinical laboratory results. 
Safety data will be reviewed on an ongoing basis by investigators and sponsor. 
The sponsor will set up regular IRC meetings (as specified in the IRC Charter). In addition, 
ad hoc IRC meetings will be triggered by reported events that contribute to pausing rules 
(see Section 7.1.1). 
If the sponsor confirms reported events fulfill pausing rules criteria: 
• The IRC will review all related data. 
• Randomization and trial treatment administration for the impacted cohort(s) will be 
paused until the IRC recommends that assignment to the cohort and administration 
of trial treatment may be resumed. 
For all trial subjects who are vaccinated, all other routine trial procedures and 
assessments, including ongoing data entry, reporting of AEs, subject-reporting of 
reactogenicity in e-diaries, blood draws, and subject follow-up, will continue during the 
pause. 
7.1.1 
Cohort trial treatment pausing rules 
In this trial AEs and SAEs will be graded for the intensity using scales based on guidance 
from the US FDA “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials” (for further details, see Section 10.4.3): 
If any of the below situations is observed in a given cohort, no further trial subjects will be 
assigned to the cohort and administration of trial treatment in the affected cohort and any 
higher DLs will be paused until IRC reviews the event(s): 
• Any SAE developed by a subject administered the combination 
BNT162b4 + BNT162b2 Bivalent or BNT162b4 + BNT162b2 Monovalent (OMI 
XBB.1.5), or BNT162b4 alone (at any DL), for which there is no alternative, 
plausible, attributable cause and which is assessed by the investigator, or the 
sponsor as possibly related. 
• Any Grade 4 AEs (solicited and/or unsolicited) after administration of combination 
BNT162b4 + BNT162b2 Bivalent or BNT162b4 + BNT162b2 Monovalent (OMI 
XBB.1.5), or BNT162b4 alone (at any DL) that is assessed as possibly related by 
the investigator, or for which there is no alternative, plausible, attributable cause. 

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• Any case of fever >40.0°C/>104.0°F for at least one daily measurement persisting 
for over 6 h despite the use of antipyretic after administration of combination 
BNT162b4 + BNT162b2 Bivalent or BNT162b4 + BNT162b2 Monovalent (OMI 
XBB.1.5), or BNT162b4 alone (at any DL) that is assessed as possibly related by 
the investigator, or for which there is no alternative, plausible, attributable cause. 
• If the IRC determines that >20% of trial subjects administered the combination 
BNT162b4 + BNT162b2 Bivalent or BNT162b4 + BNT162b2 Monovalent (OMI 
XBB.1.5), or BNT162b4 alone in the same cohort experienced the same or similar 
≥Grade 3 or above unsolicited AE (including laboratory abnormalities) considered 
related, and/or for which there is no alternative, plausible, attributable cause. 
• Any severe acute systemic hypersensitivity AE or anaphylactic reactions of Grade 3 
that occurs within 7 d of trial treatment administration for which there is no 
alternative, plausible, attributable cause. 
• Any case of myocarditis or pericarditis documented within 28 d after 
BNT162b4 + BNT162b2 Bivalent, BNT162b4 + BNT162b2 Monovalent (OMI 
XBB.1.5), or BNT162b4 alone administration with ECG or clinical laboratory 
findings supporting probable or possible myocarditis or pericarditis as per Brighton 
Collaboration Case Definition (see Section 8.3.8). 
NOTE: 
• Reactogenicity e-diary data confirmed by the investigator as being entered by the 
subject in error will not contribute toward a pausing rule. 
• Data from recipients of BNT162b2 Bivalent alone will not support the pausing rules. 
7.1.2 
Individual trial subject trial treatment pausing rules 
Trial treatment administration for an individual trial subject will be paused (if applicable), 
pending IRC review, if any of the below criteria are met: 
• Safety concerns are identified by an investigator or the IRC. 
• Permanent discontinuation (stopping) of trial treatment. 
Trial treatment administration will be permanently discontinued for an individual trial 
subject if any of the below criteria are met. 
• Any Grade 4 reactogenicity event considered to be related. 
• Pregnancy. 
• If a subject’s trial treatment assignment is unblinded prior to Visit 5. 
After pausing trial treatment according to Sections 7.1.1 or 7.1.2, the IRC may recommend 
a permanent discontinuation of trial treatment overall, in a cohort, or just for a single trial 
subject. 
A permanent discontinuation of trial treatment may also occur for non-medical reasons at 
the judgment of the investigator or the subject (i.e., subject moves to a new location). 
Trial subjects permanently discontinued from trial treatment will not be discontinued from 
the trial (i.e., will continue with trial visits and be evaluated for safety). The only exception 
is pregnant women who will not have further blood draws, but will otherwise complete all 

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planned assessments, if required including pregnancy follow-up as described in 
Section 10.5.3. 
7.1.3 
Criteria for temporarily delaying enrollment or randomization 
Enrollment or randomization into the dosing cohorts may be paused or delayed if the IRC 
recommends a pausing of trial treatment according to Sections 7.1.1 or 7.1.2. 
7.2 
Trial subject discontinuation or withdrawal from the trial 
A trial subject may be withdrawn from the trial at any time at his/her own request or may 
be discontinued from the trial at any time at the discretion of the investigator for safety, 
behavioral, compliance, or administrative reasons. 
If the trial subject withdraws consent for data processing, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
For trial subjects who withdraw consent, the investigator must clarify whether consent for 
research sample storage/processing (if given) is also withdrawn. If yes, then they must be 
informed that any research samples collected will be destroyed. The investigator must 
document research sample destruction in the Investigator’s Site File (ISF) and inform the 
sponsor about the withdrawal of consent immediately. 
If possible, permanently discontinued trial subjects should complete all assessments 
planned for the Early Termination Visit as given in the respective SoAs (Section 1.3 and 
Section 13.5). 
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 are unable to be contacted by the trial site. 
The following actions must be taken if a trial subject fails to return to the trial site for a 
required trial visit: 
• The trial site must attempt to contact the trial subject and reschedule the missed 
visit as soon as possible and counsel the trial subject on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the trial 
subject wishes to continue in the trial. 
• Before a trial subject is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the trial subject (where possible, three 
telephone calls and, if necessary, a certified letter to the trial subject’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the trial subject’s medical record. 
• If the trial subject continues to be unreachable, they will be considered to have 
withdrawn from the trial. 
7.4 
Replacement of permanently discontinued trial subjects 
Permanently discontinued trial subjects will not be replaced. 

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8 
TRIAL ASSESSMENTS AND PROCEDURES 
See the SoAs (Section 1.3 for Cohorts 1 to 4 and Section 13.5 for Cohort 5) for all planned 
timepoints for assessments. 
Trial subjects must have given informed consent (i.e., have signed and dated the ICF) 
before any trial-specific procedures are performed. 
All screening evaluations must be completed and reviewed to confirm that a trial subject 
meets all eligibility criteria before allocation to IMP (randomization). For Cohorts 1 to 4, 
subject eligibility for receipt of Dose 2 must be confirmed prior to administration of Dose 2. 
Subjects in Cohort 5 are eligible to receive Dose 1 and Dose 2 per protocol. The 
investigator will maintain a screening log to record details of all volunteers screened and to 
confirm eligibility or record reasons for screening failure (as applicable), and to avoid 
duplicate inclusion. 
Procedures conducted as part of the trial subject’s routine clinical management (e.g., 
blood count) and obtained before signing of the informed consent may be utilized for 
screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and are performed within the time frame defined in the SoAs (Section 1.3 and 
Section 13.5). 
Adherence to the trial design requirements, including those specified in the SoAs (see 
Section 1.3 and Section 13.5), is essential and required for trial conduct. Every effort 
should be made to ensure that protocol-required activities are completed as described. 
However, it is anticipated that from time to time there may be circumstances outside the 
control of the investigator that may make it unfeasible to perform the planned activity. In 
these cases, the investigator must take all steps necessary to ensure the safety and 
wellbeing of the trial subject. When a protocol-required activity cannot be performed, the 
investigator must document the reason for the missed activity and any corrective and 
preventive actions taken to ensure that required processes are adhered to as soon as 
possible. The sponsor must be informed of these incidents in a timely manner. 
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the trial. 
8.1 
Efficacy assessments 
Not applicable. 
8.2 
Safety assessments 
8.2.1 
Physical examinations 
Complete and symptom-orientated physical examinations will be performed at the 
timepoints listed in the SoAs (Section 1.3 and Section 13.5). 
• A (complete) physical examination will include, at a minimum, assessments of the 
skin, lymphatic nodes, cardiovascular, respiratory, gastrointestinal, and 
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• 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 and height and body weight 
Vital signs (comprising systolic/diastolic blood pressure, pulse rate, respiratory rate, and 
oral body temperature) will be assessed at the times given in the SoAs (Section 1.3 and 
Section 13.5). 
Vitals signs measurements should be preceded by at least 5 minutes of rest for the trial 
subject in a quiet setting without distractions (e.g., television, cell phones) and be 
measured with trial subjects in a seated position. 
Oral body temperature will be measured and recorded to one decimal place. 
Systolic/diastolic blood pressure and pulse rate measurements will be assessed with a 
completely automated device. Manual techniques will be used only if an automated device 
is not available. 
Height and body weight will be measured and recorded at screening. Height and body 
weight will be reported in cm and kg for results reporting in the ICH E3 clinical study report 
(CSR). 
8.2.3 
Electrocardiograms 
Standard 12-lead ECGs will be recorded at the times given in the SoAs (Section 1.3 and 
Section 13.5) using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and corrected QT (QTc; according to Bazett) intervals. All 
original ECG readings must be kept as source documents subject to review as needed. 
All ECGs will be judged by the investigator in terms of clinical significance. 
Any post-dose new ECGs changes which may support myocarditis/pericarditis following 
Brighton Collaboration definition such as: 
• Paroxysmal or sustained atrial or ventricular arrhythmias, 
• AV block (grade 1-3) or new bundle branch block, 
• Diffuse ST-segment elevation or PR-segment inversion, compatible with 
pericarditis, 
will trigger additional actions as described Section 12.2 and will require evaluation of the 
ECG by a cardiologist. 
Also, if a clinically significant finding is identified (including, but not limited to events listed 
above) at/or after receipt of at least one dose of trial treatment, the investigator should 
forward the ECG for evaluation by a cardiologist. This forwarding must be documented. 
For guidance on the management of symptoms that could represent myocarditis or 
pericarditis, see Section 12.2. 

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8.2.4 
Clinical laboratory tests 
Urine collection and blood draws for clinical laboratory tests will be performed at the times 
given in the SoAs (Section 10.3 and Section 13.5). For details of all assessed urine and 
blood clinical laboratory parameters, see Section 10.3. 
All protocol-required clinical laboratory tests must be conducted in accordance with the 
laboratory standard. The investigator must review the laboratory report and document this 
review with their signature and date. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the trial should be repeated until the values return to normal or baseline or 
are no longer considered clinically significant by the investigator or the trial 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. 
If laboratory values from non-protocol-specified laboratory assessments performed at the 
laboratory constitute an SAE or AE, it must be recorded as such. 
Clinical laboratory tests results will be categorized in accordance with US FDA guidance 
for industry “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials”. 
8.2.5 
Subject e-diaries for assessment of reactogenicity (local and 
systemic reactions) 
Subject e-diaries will be issued to trial subjects, trained, and collected by trial site 
personnel at the visits given in the SoAs (Section 1.3 and Section 13.5). 
Subjects will be asked to: 
• Report reactogenicity (incl. oral body temperature) daily for 7 d after each IMP dose 
using an e-diary. 
• Record the worst grade for each symptom approximately the same time every 
evening. 
• Contact the site if they experience any severe or potentially life-threatening 
reactogenicity events. 
• Report the use of antipyretic/analgesic medication to treat symptoms associated 
with IMP administration for 7 d after each IMP dose using an e-diary. 
If a local and/or systemic reaction persists beyond the end of the reactogenicity e-diary 
period following vaccination, the trial subject will be requested to report that information to 
the investigator. Solicited local and systemic events that are recorded in the subject 
e‑diaries should not be reported as AEs unless they meet criteria for an SAE or starts at 
Days 1 to 7 and continues past Day 7. 
Note: in case an e-diary entry was missed, or the e-diary did not work, the site personnel 
will ask if any reactogenicity event occurred. The site will record reported events that were 
not entered in the e-diary on the AE page of the CRF. 
8.2.5.1 
Assessments of intensity for local reactions 
Pain (perceived) at the injection site will be assessed as absent, mild, moderate, or severe 
according to the grading scale in Table 4. 

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• To report if an e-diary entry was missed or if the e-diary did not work; if any such 
events occurred, the site will record them (e.g.) on the AE page of the CRF. 
 
Investigators will review subject e-diary data daily as indicated in the SoAs (Section 1.3 
and Section 13.5). 
Only an investigator or medically qualified person is able to confirm a trial subject’s fever 
as >40.0°C/>104.0°F (a potentially life-threatening Grade 4 event) for recording in the 
electronic data capture (EDC) system. 
If a trial subject experiences confirmed Grade 4 reactogenicity, the investigator must 
immediately notify the sponsor and, if it is determined to be related to the administration of 
IMP, further IMP administration (if applicable) will be discontinued in that trial subject (see 
Section 7.1). 
If a trial subject experiences a potential Grade 4 reactogenicity, and the grading is 
confirmed by the investigator or some other medically qualified person, the confirmed 
Grade 4 reactogenicity will be recorded by the investigator as an SAE. 
8.2.7 
Assessment of local reactogenicity – Investigator tasks 
Investigators will assess acute local and systemic reactogenicity at the visits given in the 
SoAs (Section 1.3 and Section 13.5). If any acute local reactions meet any SAE criteria, 
they must be recorded as an SAE. 
8.2.8 
COVID-19 surveillance 
Surveillance of asymptomatic SARS-CoV-2 cases and “confirmed COVID-19” cases will 
be implemented in this trial. 
If a trial subject experiences symptoms consistent with COVID-19 illness they should be 
advised to contact the site immediately. If confirmed to be a potential COVID-19 illness, 
the site should schedule an unscheduled “Potential COVID-19 visit” (see the SoAs in 
Section 1.3 and Section 13.5) as soon as possible and optimally within 3 d after symptom 
onset (and at the latest after symptom resolution). 
The definition of “confirmed COVID-19” cases is based on the US FDA guidance for 
industry “Development and Licensure of Vaccines to Prevent COVID-19’’. 
Confirmed COVID-19: presence of one or more of the below symptoms and SARS-CoV-2 
nucleic acid amplification-based test (NAAT) positive test outcome during, or within 4 days 
before or after, the symptomatic period, either at the central laboratory or at a local testing 
facility (using a certified test): 
• Fever or chills 
• New or increased cough 
• New or increased shortness of breath or difficulty breathing 
• Fatigue 
• Headache 
• New or increased muscle or body aches (pain) 
• New loss of taste or smell 

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• Sore throat 
• Congestion or runny nose 
• Nausea or vomiting 
• Diarrhea 
 
Confirmed severe COVID-19 (US FDA definition): SARS-CoV-2 NAAT positive (based on 
central or local certified tests) and presence of at least one of the following: 
• Clinical signs at rest indicative of severe systemic illness (respiratory rate 
≥30 breaths per minute, heart rate ≥125 beats per minute, SpO2 ≤93% on room air 
at sea level, or PaO2/FiO2 <300 mm Hg) 
• Respiratory failure (defined as needing high-flow oxygen, noninvasive ventilation, 
mechanical ventilation, or extracorporeal membrane oxygenation) 
• Evidence of shock (SBP <90 mm Hg, DBP <60 mm Hg, or requiring vasopressors) 
• Significant acute renal, hepatic, or neurologic dysfunction 
• Admission to an intensive care unit 
• Death 
Note that: 
The US Centers for Disease Control and Prevention (CDC) list of COVID-19 symptoms 
can be found at: https://www.cdc.gov/coronavirus/2019-ncov/symptoms-
testing/symptoms.html. The symptoms listed by the CDC should not trigger a “Potential 
COVID-19 Illness Visit” unless, in the opinion of the investigator, deemed necessary. 
If new symptoms are reported within 4 d after resolution of all previous symptoms, they will 
be considered to be part of a single illness and a second illness visit is not required; 
Surveillance of potential COVID-19 symptoms should continue even if a trial subject has a 
positive SARS-CoV-2 test earlier in the trial. 
During the 7 d following the vaccination, potential COVID-19, symptoms that overlap with 
specific systemic events similar to COVID-19 infection, should not trigger a “Potential 
COVID-19 Illness Visit” unless, in the investigator’s opinion, the clinical picture is more 
indicative of a possible COVID-19 illness than vaccine reactogenicity. If, in the 
investigator’s opinion, the symptoms are considered more likely to be vaccine 
reactogenicity, or if the symptoms are equivocal, the investigator may conduct a local 
SARS-CoV-2 rapid test. If the test result is positive, the symptoms should be recorded as a 
potential COVID-19 illness; if not, the symptoms that overlap with systemic events should 
be recorded in the reactogenicity e-diary or as AEs, if not captured in the reactogenicity 
e-diary. 
The trial subject is also instructed to contact the site should they receive a positive 
SARS-CoV-2 test (NAAT or rapid antigen) to inform the site of the result and the date the 
test was conducted. 

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Potential COVID-19 Illness Visit: 
This visit should be conducted in person. Telehealth visits are not advised unless the 
investigator has sufficient justifications with no safety concerns for the trial subject. At 
minimum, the following details should be recorded by the investigator during “Potential 
COVID-19 Illness Visits”: 
• Any concomitant treatments (if any) 
• Confirmation that the trial subject does not require emergent medical care 
• Method of COVID-19 diagnosis 
• Any AEs, SAEs, AESIs, AEs leading to subject withdrawal/discontinuation 
• Outcome of the brief (symptom-directed) physical examination 
• Outcome of the rapid antigen test for SARS-CoV-2 infection 
 
8.2.8.1 
Oral swabs for NAAT-based SARS-CoV-2 testing for screening and 
surveillance 
Oral swabs for (NAAT-based) SARS-CoV-2 testing will be collected by trial site personnel 
and analyzed at a local or central laboratory as listed in the SoAs (Section 1.3 and 
Section 13.5).The devices used most commonly at trial sites come with predefined test 
panels that test for a range of pathogens and not just for SARS-CoV-2. Thus, inevitably 
and automatically, incidental data for the pathogens other than SARS-CoV-2 will be 
generated when using such devices. Since this incidental data is not required by this trial, 
only the results for SARS-CoV-2 will be recorded in the CRF, analyzed, and reported as 
described in this protocol. For test performed at trial sites, 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. 
Additionally, any potentially SARS-CoV-2-infected and/or symptomatic trial subjects will be 
asked to return ad hoc to the site for SARS-CoV-2 diagnostics as soon as possible. Oral 
swabs for SARS-CoV-2 genomic sequencing will also be collected and analyzed at a later 
timepoint at a central laboratory. 
8.2.8.2 
Serological testing for SARS-CoV-2 N-binding antibodies 
Blood will be drawn by trial site personnel for serological testing for SARS-CoV-2 
N-binding antibodies by serum SARS-CoV-2 nucleocapsid protein-specific antibody 
immunoassay at screening. 
SARS-CoV-2 nucleocapsid protein serological testing will be performed at a central 
laboratory. 
8.2.8.3 
SARS-CoV-2 sequencing 
Swabs for SARS-CoV-2 genomic sequencing storage will be collected by trial site 
personnel at the timepoints provided in SoAs (Section 1.3 and Section 13.5). 
The swabs will be inserted into collection tubes pre-filled with stabilizer solution. The 
swabs must be stored in the central laboratory at least at -70°C/-94°F until the end of the 
trial. 

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Instructions on the sample handling and shipping to the analysis site will be provided in a 
Laboratory Manual. 
The outcome of SARS-CoV-2 genomic sequencing would be SARS-CoV-2 S protein 
sequences and/or whole genome sequences and assigned (where possible) to known viral 
variants. 
8.3 
Adverse events and SAEs 
Definitions of AEs and SAEs can be found in Section 10.4. 
8.3.1 
Time period and frequency for collecting AE and SAE information 
All AE related information will be collected at the timepoints specified in the SoAs 
(Section 1.3 and Section 13.5). 
Non-serious AEs will only be collected as of first IMP dose administered while SAEs need 
to be recorded upon awareness starting once informed consent is given. 
For Cohorts 1 to 4, AE collection will start from Visit 0 and continue until Visit 4 (i.e., until 
1 month follow-up post-Dose 1), and (for subjects who consent to a second dose of IMP 
after issue of protocol version 5.0) restart from Visit 7 and continue until Visit 9 (i.e., until 
1 month follow-up post-Dose 2). 
For Cohort 5, AE collection will start from Visit 0 and continue until Visit 9 (1 month post-
Dose 2). 
AESIs, SAEs, AEs that lead to trial subject discontinuation or withdrawal, and all AEs 
linked to confirmed COVID‑19 cases will be recorded up to the last planned visit for 
subjects who consent to a second dose of IMP. For subjects in Cohorts 1 to 4 completing 
Dose 1 only, recording will continue until Visit 6 (6 months post-Dose 1). For subjects in 
Cohort 5 completing Dose 1 only, recording will continue until the last scheduled visit 
(5 months post-Dose 1). 
Medical occurrences that begin after obtaining informed consent but before the start of trial 
treatment administration must be recorded on the respective Medical History/Current 
Medical Conditions section of the CRF and not in the AE section unless they qualify as 
SAEs. 
Medical occurrences meeting the criteria for an SAE (see Section 10.4.2) must be reported 
as SAEs (see Section 8.3.4). 
8.3.2 
Detecting and reporting AEs and SAEs 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of AEs or SAEs, and remain responsible for 
following up all AEs and SAEs. The investigator will record on the CRF all AEs and SAEs 
observed directly and all AEs and SAEs spontaneously reported by the trial subject. 
Open-ended and non-leading verbal questioning of the trial subject is the preferred method 
to inquire about AE occurrences. Care will be taken not to introduce bias when detecting 
AEs and/or SAEs. 
Guidance for the recording, evaluating, and assessing of AEs and SAEs is provided in 
Section 10.4. 

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For grading the severity of AEs and SAEs, the US FDA “Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” will be 
used. 
Investigators are not obligated to actively seek AE or SAE 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 related (see Section 10.4) to the trial treatment or trial participation, the investigator 
must promptly notify the sponsor as described in Section 10.4.4. 
The investigator may be requested by the sponsor to obtain specific follow-up information 
in an expedited fashion. 
All SAEs (initial and follow-up reports) will be recorded and reported to the sponsor or 
designee within 24 h after the site becoming aware of the event, as indicated in 
Section 10.4.4. 
For real time monitoring of events which contribute to pausing rule criteria (see 
Section 7.1.1), all such events (even if non-serious) need to be reported on the SAE form 
within 24 h of awareness as described in Section 10.4.4. 
AESIs have been defined in this trial. For how to report AESIs, see Section 8.3.8. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow up with 
each trial subject at subsequent visits/contacts. 
All AEs and SAEs will be followed up until resolution, stabilization, the event is otherwise 
explained, or the trial subject is lost to follow-up, or the trial subject withdraws consent (as 
defined in Section 7.3). If no final status is reached by the last planned follow-up visit, the 
investigator must confirm the unavailability of a final status. Further information on follow-
up procedures is provided in Section 10.4.2.2. 
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 health care professionals. 
New or updated information will be recorded in the originally completed CRF. 
If a trial subject dies during participation in the trial or during a predefined follow-up period 
(see the SoAs in Section 1.3 and Section 13.5), the investigator will provide the sponsor a 
copy of any postmortem findings including histopathology. 
The investigator will submit initial and follow-up SAE reports to the sponsor or designee 
within 24 h after the site becoming aware of the event, as indicated in Section 10.4.4. 
8.3.4 
Reporting requirements for SAEs including SUSARs 
Prompt notification of an SAE via an EDC system and/or the provided SAE form by the 
investigator to the sponsor within 24 h of the site’s awareness is essential so that the 
ethical responsibilities to trial subjects, the safety of a trial treatment under clinical 
investigation, and regulatory reporting obligations can be met. 

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The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies involved in the conduct of trials with the same IMP 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, Institutional 
Review Boards (IRBs)/Independent Ethics Committees (IECs), and investigators. The 
execution of reporting to the different entities may be delegated as detailed in the trial-
specific Safety Management Plan. 
All serious adverse reactions where the nature, severity or outcome is not consistent with 
the reference safety information are “unexpected serious adverse reactions”. The 
expectedness assessment for all related SAEs is based on the reference safety 
information included in Section 6.1.5 of the BNT162 IB and the BNT162b4 IB. 
All suspected adverse reactions related to an IMP (the tested drugs and comparators) that 
occur in this trial, and that are both unexpected and serious, qualify as SUSARs. SUSARs 
are subject to expedited reporting by the sponsor according to applicable regulatory 
requirements and guidance (i.e., ICH E2A guidance). Information about analysis of similar 
events will be added to the SUSAR report. IRBs/IECs will receive SUSAR reports as 
applicable. 
8.3.5 
Pregnancy testing and handling of pregnancies 
For VOCBP, pregnancy tests will be performed at the times given in the SoAs (Section 1.3 
and Section 13.5). 
For all trial subjects, pregnancy information will be collected over the time period defined in 
SoAs (Section 1.3 and Section 13.5). 
Any female trial subject who becomes pregnant while participating in the trial will need to 
discontinue the IMP immediately. 
Pregnancy information will only be collected after obtaining written informed consent from 
the pregnant female trial subject (or if a male trial subjects’ partner becomes pregnant, 
written informed consent from the trial subjects’ partner). 
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 10.5.3. 
Pregnancy per se is not an AE (and hence not an SAE). Abnormal pregnancy outcomes 
(e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic 
pregnancy) are considered SAEs. 
As described in Section 7.1.2, trial subjects who become pregnant will be permanently 
discontinued from trial treatment and will not have further blood draws, but will otherwise 
complete all planned assessments, if required including pregnancy follow-up as described 
in Section 10.5.3. 
8.3.6 
Death events 
Any death that occurs within the observation period will be reported as an SAE, if not 
covered by the exemptions to the SAE definition as defined in Sections 8.3.7, 10.4.2, and 
10.4.2.2, which do also apply for fatal cases. Date and cause of death will be recorded. If 
available, a copy of an autopsy report should be submitted upon request. 

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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 the outcome “fatal” (death) 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. 
In addition to reporting as SAE, the death page of the CRF needs to be completed. 
8.3.7 
Disease-related events/outcomes not qualifying as AEs or SAEs 
Not applicable. 
8.3.8 
Adverse events of special interest (AESIs) 
An AESI, serious or non-serious, is one of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and rapid communication by 
the investigator to the sponsor are appropriate. Such an event might warrant further 
investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the trial sponsor to other parties (e.g., regulators) might 
also be warranted. 
The following will be reported as AESIs: 
• Anaphylaxis 
• Thromboembolic events (e.g., deep vein thrombosis, stroke, myocardial infarction) 
• Immune thrombocytopenia 
• Immune-based neurologic events (e.g., optic neuropathy, Guillain-Barré syndrome) 
• Myocarditis (all Levels of Certainty including “Possible cases” (1 to 3) as per 
Brighton Collaboration Case Definition), 
https://brightoncollaboration.org/myocarditis/ 
• Pericarditis (all Levels of Certainty including “Possible cases” (1 to 3) as per 
Brighton Collaboration Case Definition), 
https://brightoncollaboration.org/myocarditis/ 
All symptoms that could represent myocarditis or pericarditis should be reported within 
24 h of awareness using the dedicated Myocarditis or Pericarditis AESI Report Form and 
reporting to the contact details provided in Section 10.4.4. For guidance on the 
management of symptoms that could represent myocarditis or pericarditis, see 
Section 12.2. 
All other AESIs, excluding myocarditis and pericarditis, (even if non-serious), should be 
reported within 24 h of awareness as well, using the AESI Report Form and reporting to 
the contact details provided in Section 10.4.4. However, if such AESI meets the serious 
criteria, it must be reported on the SAE form within 24 h of awareness as described in 
Section 10.4.4. 
All AESIs will be followed up until resolution, stabilization, the event is otherwise explained, 
or the trial subject is lost to follow-up (as defined in Section 7.3). 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
Tri al n u m b er: B N T 1 6 2 -2 1  
P a g e 7 1  of 1 1 8  
V er si o n: 8. 0  
D at e: 1 6 S E P 2 0 2 4  
 
 
8. 4  
Pr o c e d ur e s i n c a s e of o v er d o s e or err or s  i n I M P a d mi ni str ati o n  
F or a d efi niti o n of a n o v er d o s e a n d err or s i n I M P a d mi ni str ati o n, s e e S e cti o n  1 0. 4. 1. 3. 3 . 
F or t h e r e p orti n g of t h e s e e v e nt s, s e e S e cti o n 1 0. 4. 1. 3. 3 . 
T h e s p o n s or d o e s n ot r e c o m m e n d s p e cifi c tr e at m e nt f or a n o v er d o s e.  
I n t h e e v e nt of a n o v er d o s e or a n err or i n I M P a d mi ni str ati o n, t h e i n v e sti g at or s h o ul d:  
•  C o nt a ct t h e tri al M e di c al M o nit or i m m e di at el y.  
•  ( At t h e di s cr eti o n of t h e i n v e sti g at or) Gi v e s y m pt o m ati c tr e at m e nt. 
•  Cl o s el y m o nit or t h e tri al s u bj e ct f or a n y A E/ S A E a n d l a b or at or y a b n or m aliti e s ( at 
l e a st 7  d).  
•  D o c u m e nt t h e q u a ntit y of t h e e x c e s s d o s e a s w ell a s t h e d ur ati o n of t h e o v er d o s e 
i n t h e C R F. 
•  D o c u m e nt t h e err or i n I M P a d mi ni str ati o n . 
 
F or  c a s e s  of err or s i n I M P a d mi ni str ati o n , t h e tri al M e di c al M o nit or , i n c o or di n ati o n wit h t h e 
tri al s af et y t e a m, will d e ci d e o n h o w t h e e v e nt s  s h o ul d b e c a pt ur e d i n t h e d at a b a s e , a n d 
s u g g e st  a p pr o pri at e c orr e cti v e a n d/ or pr e v e nti v e a cti o n s . 
D e ci si o n s r e g ar di n g d o s e i nt err u pti o n s or m o difi c ati o n s will b e m a d e b y t h e i n v e sti g at or i n 
c o n s ult ati o n wit h t h e  tri al M e di c al M o nit or b a s e d o n t h e cli ni c al e v al u ati o n of t h e tri al 
s u bj e ct  c o n c er n e d . 
8. 5  
P h ar m a c o ki n eti c s  
P h ar m a c o ki n eti c p ar a m et er s ar e n ot e v al u at e d i n t hi s tri al.  
8. 6  
G e n eti c s  
F or s u bj e ct s f or w h o m a 
s a m pl e i s o bt ai n e d , a bl o o d s a m pl e f or g e n eti c r e s e ar c h 
will b e dr a w n at t h e ti m e s li st e d i n t h e S o A s  ( S e cti o n 1. 3  a n d  S e cti o n  1 3. 5 ).
8. 7  
I m m u n e r e s p o n s e s 
H u m or al a n d c ell ul ar i m m u n e r e s p o n s e s  will b e a s s e s s e d a s pl a n n e d i n S e cti o n  3 ; s e e 
al s o  t h e S o A s  (S e cti o n  1. 3  a n d  S e cti o n  1 3. 5 ).  
I n str u cti o n s o n t h e s a m pl e c oll e cti o n, h a n dli n g, a n d s hi p pi n g will b e pr o vi d e d i n a 
L a b or at or y M a n u al.  
H u m or al i m m u n e r e s p o n s e a s s e s s m e nt s will i n cl u d e:  
C CI
C CI
C CI

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
Tri al n u m b er: B N T 1 6 2 -2 1  
P a g e 7 2  of 1 1 8  
V er si o n: 8. 0  
D at e: 1 6 S E P 2 0 2 4  
 
 
•  G M T s  at b a s eli n e a n d 2 8  d aft er e v er y I M P d o s e a n d s er or e s p o n s e s . Ot h er 
ti m e p oi nt s m a y b e a s s e s s e d ( s e e t h e
 
•  C h ar a ct eri z ati o n  of tit er s a n d ki n eti c s of a nti g e n -bi n di n g a nti b o di e s a n d f u n cti o n alit y 
of a nti g e n -s p e cifi c s er u m  a nti b o di e s u si n g li g a n d-bi n di n g - a n d vir u s n e utr ali z ati o n 
t e st s. 
8. 7. 1  
E x pl or at or y r e s e ar c h  
Bi o s a m pl e s f or r e s e ar c h will b e r et ai n e d f or u s e f or u p t o 1 5  yr s ( or s h ort er if r e q uir e d b y 
l o c al r e g ul ati o n s) aft er t h e e n d of t h e tri al. T h e t u b es  wit h t h e bi o s a m pl e s  will b e l a b el e d 
C CI
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9.4.2 
Primary safety endpoints 
The safety endpoints are defined in Sections 3 and 13.6. All safety analyses will be based 
on the Safety Set. 
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 and PT for each AE. 
Reactogenicity 
Solicited local reactions and systemic events (from the subject e-diary or the AE CRF) will 
be summarized. In general, solicited reactions will be analyzed for each IMP 
administration, i.e.: 
• Up to 7 d after each IMP injection 
For each IMP administration, the number and percentage of subjects reporting at least one 
local reaction or systemic reaction (i.e., solicited data collected using subject e-diaries or 
the AE CRF) will be summarized for each of the following types: 
• Any local reactions or systemic events 
• Local reactions or systemic events by maximum severity 
. 
Adverse events 
All AEs recorded by the investigator are unsolicited events. The number and percentage of 
subjects reporting at least one AE from Dose 1 will be summarized by PT nested within 
system organ class for each of the following AE types (for subjects with at least one AE 
occurring up to 28 d after each IMP administration, and for subjects in Cohorts 1 to 4 with 
at least one SAE occurring up to 6 months after each IMP administration and for subjects 
in Cohort 5 with at least one SAE occurring up to 3 months after last IMP administration): 
• Any AE 
• Grade of AE 
• Related AE 
• Related Grade ≥3 AE 
• Any SAE 
• Related SAE 
• Any AESI 
• Related AESI 
Moreover, the number and percentage of subjects with any AE will be summarized by 
worst grade by PT nested within system organ class. 
Additional safety analyses may be described in the SAP. 
9.4.3 
Secondary immunogenicity endpoints 
The secondary endpoints are defined in Sections 3 and 13.6. 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
Tri al n u m b er: B N T 1 6 2 -2 1  
P a g e 7 6  of 1 1 8  
V er si o n: 8. 0  
D at e: 1 6 S E P 2 0 2 4  
 
 
C o h ort s  1 t o 4  
G e o m etri c m e a n tit er s ( G M T s ) of S A R S -C o V -2 a n c e str al str ai n a n d O mi cr o n n e utr ali zi n g 
a nti b o d y  wit h a s s o ci at e d 9 5 % c o nfi d e n c e i nt er v al ( CI ) will b e c al c u lat e d  at e a c h ti m e p oi nt 
a s t h e m e a n of t h e a s s a y r e s ult s aft er m a ki n g t h e  l o g arit h m tr a n sf or m ati o n a n d t h e n 
e x p o n e nti ati n g t h e m e a n t o e x pr e s s r e s ult s o n t h e ori gi n al  s c al e. T w o -si d e d 9 5 % CI s will 
b e o bt ai n e d b y t a ki n g l o g tr a n sf or m ati o n s of a s s a y r e s ult s,  c al c ul ati n g t h e 9 5 % CI wit h 
r ef er e n c e t o t h e St u d e nt t di stri b uti o n, a n d t h e n e x p o n e nti ati n g t h e c o nfi d e n c e li mit s. 
G e o m etri c m e a n f ol d ri s e s ( G M F R ) of S A R S -C o V -2 a n c e str al str ai n a n d O mi cr o n 
n e utr ali zi n g a nti b o d y wit h a s s o ci at e d 9 5 % CI will b e c al c u lat e d at e a c h ti m e p oi nt. G M F R s 
ar e d efi n e d a s r ati o s of t h e r e s ult s aft er v a c ci n ati o n t o t h e r e s ult s b ef or e v a c ci n ati o n  ( pr e-
D o s e  1) . G M F R s will b e c al c ul at e d a s t h e m e a n of t h e diff er e n c e of l o g arit h mi c all y 
tr a n sf or m e d a s s a y r e s ult s (l at er ti m e p oi nt mi n u s e arli er ti m e p oi nt) a n d e x p o n e nti ati n g t h e 
m e a n. T h e a s s o ci at e d 2 -si d e d 9 5 % CI s will b e o bt ai n e d b y c o n str u cti n g CI s u si n g  t h e 
St u d e nt t di stri b uti o n f or t h e m e a n diff er e n c e o n t h e l o g arit h m s c al e a n d e x p o n e nti ati n g t h e 
c o nfi d e n c e li mit s.  
S er or e s p o n s e i s d efi n e d a s a c hi e vi n g ≥4 -f ol d ri s e fr o m b a s eli n e (pr e -D o s e  1). If t h e 
b a s eli n e m e a s ur e m e nt i s b el o w l o w er li mit of q u a ntit ati o n (L L O Q ), t h e p o st v a c ci n ati o n 
m e a s ur e of ≥4 × L L O Q i s c o n si d er e d s er or e s p o n s e.  T h e c o u nt s, p er c e nt a g e s a n d 
a s s o ci at e d Cl o p p er -P e a r s o n 9 5 % CI of s u bj e c t s wit h s er or e s p o n s e at e a c h ti m e p oi nt will 
b e pr o vi d e d.  
F urt h er d et ail s of t h e s e c o n d ar y  i m m u n o g e ni cit y a n al y s e s will b e d e s cri b e d i n t h e S A P. 
9. 4. 5  
Ot h er s af et y a n al y s e s  
D et ail s of t h e ot h er s af et y a n al y s e s will b e d e s cri b e d i n t h e S A P.  
9. 4. 6  
Ot h er a n al y s e s  
Ot h er a n al y s e s will b e d e s cri b e d i n t h e S A P.  
9. 5  
I nt eri m a n al y s e s 
A s t hi s i s a n o b s er v er -bli n d P h a s e  I tri al, t h e s p o n s or m a y c o n d u ct u n bli n d e d r e vi e w s of 
t h e d at a d uri n g t h e c o ur s e of t h e tri al ( e. g., at 7 d a n d 2 8  d aft er e a c h I M P a d mi ni str ati o n) 
f or t h e p ur p o s e of s af et y a s s e s s m e nt, f a cilit ati n g d o s e e s c al ati o n d e ci si o n s, a n d/ or 
s u p p orti n g cli ni c al d e v el o p m e nt. F or f urt h er d et ail s, s e e t h e S A P.  
1 0  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  
1 0. 1  
R e g ul at or y, et hi c al, a n d tri al o v er si g ht c o n si d er ati o n s  
T hi s tri al will b e c o n d u ct e d i n a c c or d a n c e wit h t hi s pr ot o c ol, t h e et hi c al pri n ci pl e s t h at h a v e 
t h eir ori gi n i n t h e D e cl ar ati o n of H el si n ki, I C H G o o d Cli ni c al Pr a cti c e ( G C P ) g ui d eli n e s, a n d 
a p pli c a bl e l a w s a n d r e g ul ati o n s.  
C CI

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10.1.1 
Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• Applicable ICH GCP Guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents, will be 
submitted to the relevant regulatory authorities as required by applicable regulations. If 
required, approval for conducting the trial will be obtained from regulatory authorities in 
accordance with relevant regulatory requirements. 
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) will be submitted to an IRB/IEC and reviewed and approved by the 
IRB/IEC before the trial is initiated. 
Any amendments to the protocol will be submitted for IRB/IEC approval and (if required) 
competent authority approval before implementation of changes made to the trial design, 
except for changes necessary to eliminate an immediate hazard to trial subjects. 
The principal investigator or delegate will be responsible for the following: 
• Providing written summaries of the status of the trial to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• Providing oversight of the conduct of the trial at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 (if applicable), and all other applicable local regulations. 
• Informing the sponsor immediately about any urgent safety measures taken by the 
investigator to protect the trial subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP that the investigator becomes 
aware of (see Section 10.1.13). 
The principal investigator, any investigator(s), the sponsor, or personnel at other 
establishments, must cooperate with any inspection of the documents, facilities, records, 
and other resources deemed appropriate by the inspecting authorities to be related to the 
trial and that may be located at the trial site, at the sponsor, or at other establishments. 
The sponsor must be notified as soon as possible about any upcoming regulatory authority 
inspection. 
10.1.2 
Financial disclosure 
All investigators will provide the sponsor with sufficient, accurate financial information as 
requested to allow the sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are 

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responsible for providing information on financial interests during the course of the trial and 
for 1 yr after completion of the trial. 
10.1.3 
Informed consent process 
Informed consent must be obtained before any trial-specific screening procedure is 
performed. For subjects in Cohorts 1 to 4 consenting to a second dose of IMP and trial 
procedures as implemented by protocol version 5.0, informed consent must also be 
obtained before any procedures implemented by protocol version 5.0 are performed. 
Trial subjects must be informed that their participation is voluntary. 
The investigator will explain the nature of the trial to the trial subject and answer all 
questions regarding the trial. 
Trial subjects will be required to sign and date a statement of informed consent that meets 
the requirements of local regulations (e.g., 21 CFR 50), ICH GCP guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and 
the IRB/IEC or trial site. 
The medical record must include a statement that written informed consent (including 
version and type of ICF) was obtained before the trial subject was enrolled in the trial and 
the date the written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF. 
Trial subjects must be informed in a timely manner if new information becomes available 
that may impact their willingness to participate in the trial. If required, trial subjects will be 
reconsented to updated written information and consent forms. 
Trial subjects who are rescreened must re-consent. 
A copy of the ICF(s) must be provided to the trial subject. 
10.1.4 
Data protection 
All data collected and processing during this trial will be performed in accordance with the 
applicable data protection requirements. 
Trial subject personal data will be stored at the trial site in encrypted electronic and/or 
paper form and will be password protected or secured in a locked room to ensure that only 
authorized trial personnel have access. The trial site will implement appropriate technical 
and organizational measures to ensure that the personal data can be recovered in the 
event of disaster. In the event of a potential personal data breach, the trial site will be 
responsible for determining whether a personal data breach has in fact occurred and, if so, 
providing breach notifications as required by law. 
Trial subjects will be assigned a unique identifier by the investigator according to the 
sponsor specifications on unique identifier assignment. The trial site will maintain a 
confidential list of trial subjects who participated in the trial, linking each trial subject’s 
unique identifier to his or her actual identity and medical record identification. 
Any trial subject records or datasets that are transferred to the sponsor will contain the 
identifier only; trial subject names or any information which would make the trial subject 
identifiable will not be transferred. 
The trial subject must be informed that their personal trial-related data will be used by the 
sponsor in accordance with local data protection laws. The level of disclosure must also be 

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explained to the trial subject who will be required to give consent for their data to be used 
as described in the informed consent. 
The trial subject must be informed that their medical records may be examined by sponsor 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
If the trial subject withdraws from the trial and/or withdraws consent for disclosure of future 
information, the sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. When trial subject data are to be deleted, the investigator will 
ensure that all copies of such data are promptly and irrevocably deleted from all systems. 
10.1.5 
Committees – IRC 
A trial IRC will be established to provide medical oversight of trial subject safety during the 
conduct of this trial, with a focus on guidance, management of emergent safety issues, 
and decision making as outlined in the IRC Charter. It includes periodic in-depth review of 
safety data by trial subject, cohort, and cumulatively, in order to confirm mechanism of 
action, identify potential off-target toxicities, and to understand the IMP’s safety profile and 
feasibility for further clinical development. The IRC is also a forum for the discussion of 
other data which could impact the IMP benefit-risk assessment, thereby allowing the IRC 
to periodically assess the overall benefit-risk of the IMP. 
All SAEs considered related either by the investigator or the sponsor will trigger an ad hoc 
review by the IRC. 
The IRC will be constituted and act according to procedures described in the IRC Charter. 
The charter will define suitable measures to maintain the blinding described in 
Section 6.3.2. The IRC will prepare written minutes of its meetings. Documentation of IRC 
activities will be filed in the trial master file. 
10.1.6 
Dissemination of clinical trial data 
A final ICH E3 conform report integrating all trial results will be prepared by the sponsor. 
In all cases, trial results will be reported in an objective, accurate, balanced, and complete 
manner and are reported regardless of the outcome of the trial or the country in which the 
trial was conducted. 
Clinical trial data and documentation will be disseminated as required per applicable laws 
and regulations, e.g., the European Union (EU) Regulation No 536/2014, EU Regulation 
1049/2001, and the US Final Rule, which implements Section 801 of the Food and Drug 
Administration Amendments Act (FDAAA 801). Clinical documents under such laws 
includes protocols and protocol amendments, SAPs, and ICH E3 CSRs. 
This trial will be registered, and trial results be publicly posted, on publicly accessible trial 
registries (e.g., ClinicalTrials.gov, EU Clinical Trials Register, etc.) as required per 
applicable laws and regulations. 
If this clinical trial is used to support marketing authorization packages/submissions, the 
sponsor will comply with the EU Policy 0070, the proactive publication of clinical data on 
the EMA website. Clinical data, under Phase I of this policy, includes clinical overviews, 
clinical summaries, ICH E3 CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. under Phase II of this policy, “clinical 
data” includes the publishing of individual patient data. 

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Even if not required by applicable laws and regulations, this trial will be registered, and trial 
results be publicly posted on ClinicalTrials.gov. In addition, expert summaries of the 
outcomes for all primary and secondary outcome measures (irrespective of outcome) and 
lay summaries, will be posted on a publicly accessible website. 
The sponsor may provide researchers secure access to subject-level data, expert 
summaries, lay summaries, and CSRs for the purposes of “bona fide scientific research” 
that contributes to the scientific understanding of the disease, target, or compound class. 
In these cases, all trial patient level data will be anonymized in accordance with applicable 
privacy laws and regulations. 
The results for all primary and secondary outcome measures, irrespective of outcome, will 
be submitted for publication in academic journals (for further details, see Section 10.1.9). 
10.1.7 
Data quality assurance 
All trial subject data relating to the trial will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities and requirements, including handling of non-compliance issues 
and monitoring techniques (central, remote, or on site monitoring) are provided in the 
Monitoring Plan. 
The sponsor or designee is responsible for the data management of this trial including 
quality checking of the data. 
The sponsor assumes accountability for actions delegated to other parties (e.g., CRO). 
Ongoing source data verification will be performed to confirm that data entered into the 
CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of trial subjects are being protected; and that the trial 
is being conducted in accordance with the currently approved protocol and any other trial 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this trial must 
be retained by the investigator in accordance with relevant local requirements after trial 
completion unless institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor. 
10.1.8 
Source documents 
Source documents provide evidence for the existence of the trial subject and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 

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Data reported on the CRF or entered in the CRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the trial. Also, current medical records must be available. 
Source data are all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents 
(original records or certified copies). 
Source documents are original documents, data, and records (e.g., hospital records, 
clinical and office charts, laboratory notes, memoranda, subject diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, trial subject files, and 
records kept at the pharmacy, at the laboratories and at medico-technical departments 
involved in the clinical trial). 
10.1.9 
Publication policy 
The results for all primary and secondary outcome measures, irrespective of outcome, will 
be submitted by the sponsor for publication in academic journals. The results of this trial 
may also be presented by the sponsor at scientific meetings. 
The results of this trial may be published or presented at scientific meetings by the 
investigator. If this is foreseen, the investigator agrees to submit all manuscripts or 
abstracts to the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. The investigator will, on request, remove any 
previously undisclosed confidential information before disclosure, except for any trial 
treatment-related information necessary for the appropriate scientific presentation or 
understanding of the trial results. 
Unless agreed in advance otherwise, site- or subpopulation-specific analyses may only be 
published after the outcomes of the primary endpoint analyses have been published. 
The sponsor will comply with applicable requirements for publication of trial results. In 
accordance with standard editorial and ethical practice, including those established by the 
International Committee of Medical Journal Editors (ICJME). The sponsor will generally 
support publication of multi-site trials only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with ICJME authorship 
requirements. 
10.1.10 Protocol preparation and approval 
This protocol has been prepared, reviewed and approved in accordance with the sponsor’s 
standard operating procedures. Documentation of this process is filed in the trial master 
file. 
10.1.11 Investigators and trial administrative structure 
10.1.11.1 
Investigators and trial site personnel 
There must be an investigator at each trial site. 

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If the trial is conducted by a team of individuals at the trial site, the investigator leading and 
responsible for the team is called the principal investigator. 
The responsibilities of principal investigator(s) must be documented before any trial-related 
procedure is performed. All persons assigned responsibility as principal investigator must 
sign a declaration of their responsibilities. They must also sign a declaration that they have 
read and understand the content of the protocol, that all questions have been adequately 
answered, and that they are qualified by experience and training to act as investigator for 
this trial. 
The principal investigator at each trial site is responsible for ensuring that this trial is 
conducted in accordance with the protocol, the principles of GCP, and applicable 
regulatory requirements. 
If the trial is conducted at multiple trial sites, a coordinating investigator must be assigned 
who is responsible for the coordination of investigators at different trial sites. The 
responsibilities of the coordinating investigator must be documented before any trial-
related procedure is performed. 
Documentation of all involved investigators must be maintained according to ICH GCP and 
applicable regulatory requirements. 
Curriculum vitae and/or other relevant documents confirming the current qualification of 
the investigators must be provided to the sponsor. This should include any previous 
training in the principles of GCP, experience obtained from work with clinical trials, and 
experience with medical care. 
10.1.11.2 
Trial site personnel assigned trial-related duties 
The principal investigator may define appropriately qualified personnel at a trial site to 
perform significant trial-related procedures and/or to make trial-related decisions under 
their supervision. In this case, the principal investigator must maintain a signed list of the 
persons to whom they delegate significant trial-related duties/responsibilities; the 
delegated trial-related duties/responsibilities must be specified in the list. 
When personnel or responsibility changes are made, the principal investigator must 
ensure that the relevant documentation is updated before any trial-related activities are 
performed. 
Documentation of all involved trial site personnel performing significant trial-related 
procedures and/or making trial-related decisions must be maintained according to GCP 
and applicable regulatory requirements. 
10.1.11.3 
Contract research organizations 
Documentation of all involved CRO must be maintained according to GCP and applicable 
regulatory requirements. This includes documentation of any delegation of responsibilities 
to CROs. 
10.1.11.4 
The sponsor and sponsor’s personnel 
The trial sponsor listed on the title page accepts the responsibilities of the sponsor 
according to GCP and applicable regulatory requirements. 

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The sponsor will designate appropriately qualified personnel to advise on trial-related 
topics. The trial site will be provided with contact details for these personnel before any 
trial-related procedure is performed. 
A list of key sponsor personnel involved in the preparation of this protocol and the conduct 
of the trial, including their full names, titles, roles, and responsibilities, will be maintained. 
Some sponsor tasks may be delegated, e.g., to CRO staff. Documentation of any 
delegation of responsibilities will be maintained. 
10.1.12 Premature termination or suspension of the trial 
If the trial is prematurely terminated or suspended for any reason, the investigator should 
promptly inform the trial subjects, should assure appropriate therapy and follow-up for the 
subjects, and, where required by the applicable regulatory requirement(s), should inform 
the regulatory authorities. In addition: 
If the investigator terminates or suspends a trial without prior agreement of the sponsor, 
the investigator should inform the institution where applicable, and the investigator should 
promptly inform the sponsor and the IRB/IEC and should provide the sponsor and the 
IRB/IEC a detailed written explanation of the termination or suspension. 
Reasons for the early closure of a trial site by the sponsor may include (but are not limited 
to): 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, applicable sponsor procedures, or the ICH GCP 
guidelines. 
• Inadequate recruitment of trial subjects by the investigator. 
• Discontinuation of further IMP development based on sponsor decision. 
• If the trial is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any CROs 
used in the trial of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The investigator should promptly inform the trial 
subject and should assure appropriate therapy and/or follow-up (if applicable). 
If the IRB/IEC terminates or suspends its approval/favorable opinion of a trial, the 
investigator should inform the institution where applicable and the investigator should 
promptly notify the sponsor and provide the sponsor with a detailed written explanation of 
the termination or suspension. 
10.1.13 Reporting of serious breaches 
A serious breach is any deviation from the approved protocol version that is likely to affect 
to a significant degree the safety of a trial subject and/or the rights of trial subjects and/or 
the reliability and robustness of the data generated in the clinical trial. 
Trial sites, including pharmacists, CROs and other designees of the sponsor, must report 
any suspected serious breaches promptly to the sponsor. Suspected serious breaches, as 
well as any communication related to suspected serious breaches, must be reported to the 
sponsor by e-mail using the following e-mail address within 24 hours of knowledge: 
•

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The sponsor will assess each suspected serious breach to decide whether it should be 
reported as a serious breach. The sponsor will comply with country-specific regulatory 
requirements relating to the reporting of serious breaches to regulatory authorities and 
IRBs/IECs. 
10.2 
Data collection and management 
The trial documentation must be adequate for the reconstruction of the trial. 
10.2.1 
Data management 
The CRO will be responsible for data management of this trial, including quality checking 
of the data. 
Data entered manually will be submitted to the sponsor through use of an EDC system, 
data extracts, and reports. Trial sites will be responsible for data entry into the EDC 
system. In the event of discrepant data, the CRO will request data clarification from the 
trial sites, which the trial sites will resolve electronically in the EDC system. 
The CRO will produce a Trial Data Validation Specification document that describes the 
quality checking to be performed on the data. CRFs and correction documentation will be 
maintained in the EDC system’s audit trail. 
System backups for data stored by the sponsor and records retention for the trial data will 
be in accordance with regulatory requirements. 
At the end of the trial, the investigator will receive trial subject data for their trial site in a 
readable format that must be kept with the trial records. Acknowledgment of receipt of the 
trial subject data will be obtained. 
10.2.2 
Case report forms 
CRFs will be completed through the use of an EDC system. Trial site personnel will 
receive training and have access to a manual for appropriate CRF completion. The CRFs 
should be handled in accordance with instructions and be submitted electronically to the 
sponsor via the system. 
All CRFs should be completed by designated, trained trial site personnel. CRFs should be 
reviewed, verified, and then electronically signed and dated by the investigator or a 
designee. 
10.2.3 
Subject-reported outcomes 
Subject e-diaries will be used for the reporting of reactogenicity (local and systemic 
reactions) by the trial subjects. See Section 8.2.5 for details (for e-diaries). 
10.2.4 
Investigator’s Site File and the Trial Master File 
The principal investigator is responsible for the filing of all essential documents in an ISF. 
The sponsor is responsible for the timely filing of all essential documents in the trial master 
file. As applicable, these files must be available at monitoring visits and during audits or 
regulatory inspections. 
After trial completion, the principal investigator must ensure that all source 
data/documentation related to the trial is recorded, handled, and stored in a way that 

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allows its accurate reporting, interpretation and verification. The principal investigator must 
take measures to prevent accidental or premature destruction of these documents. 
The principal investigator must keep the ISF, the source data/documentation arising from 
the trial according to the prescribed record retention period in the country and/or according 
to the hospital policy, but at least until informed by the sponsor that the trial-related records 
are no longer required. 
10.3 
Clinical laboratory tests 
Blood/urine sampling for clinical laboratory tests will be performed at the time/days listed in 
the SoAs (Section 1.3 and Section 13.5). 
The clinical laboratory tests are: 
• Chemistry: alkaline phosphatase, alanine transaminase, creatinine, C-reactive 
protein, albumin, amylase, aspartate transaminase, gamma glutamyl 
transpeptidase, total bilirubin, indirect and direct bilirubin, blood urea nitrogen, 
glucose, lipase, cardiac troponin I. 
• Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count 
and differential (absolute and %; neutrophils, lymphocytes, monocytes, eosinophils, 
basophils), platelet count. 
o Women who are VOCBP will be measured for serum β-HCG at Visit 0. 
o Women who are not VOCBP will be measured for follicle stimulating 
hormone (FSH) at Visit 0 (to confirm postmenopausal status). 
• 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. 
Additional tests may be performed (including the addition of parameters) at any time 
during the trial as determined necessary by the investigator or required by local 
regulations. 
10.4 
Adverse events: Definitions and procedures for recording, 
evaluating, follow-up, and reporting 
10.4.1 
Definition of AEs 
• An AE is any untoward medical occurrence in a trial subject administered a 
pharmaceutical product, which does not necessarily have to have a causal 
relationship with this treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product, whether or not 
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10.4.1.1 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. 
• New conditions diagnosed after the date informed consent was given (ICF signed 
and dated) but before the first administration of trial treatment, that meet the criteria 
for SAEs. 
• New conditions diagnosed after the first administration of trial treatment. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or severity of the condition. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either trial 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE. 
10.4.1.2 
Events not meeting the AE definition 
• (This trial will allow enrollment of healthy volunteers with pre-existing stable 
disease) Any clinically significant abnormal laboratory findings or other abnormal 
safety assessments which are associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the trial subject’s 
condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur or continue 
(social and/or convenience admission to a hospital). 
• New conditions diagnosed after the date informed consent was given (ICF signed 
and dated) but before the first administration of trial treatment that does not meet 
the criteria for an SAE. 
• (This trial will allow enrollment of healthy volunteers with pre-existing stable 
disease) Anticipated day-to-day fluctuations of pre-existing disease(s) or 
condition(s) present or detected at the start of the trial that do not worsen. 
• (This trial will allow enrollment of healthy volunteers with pre-existing stable 
disease) Disease-related events and/or disease-related outcomes not qualifying as 
AEs or SAEs are further specified in Section 8.3.7. 
10.4.1.3 
Documentation of particular situations 
10.4.1.3.1 
AEs that are secondary to other events 
In general, AEs that are secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events. A medically significant secondary AE that is separated in time 
from the initiating event should be documented as an independent AE in source data and 
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If vomiting results in mild dehydration with no additional treatment in a healthy adult, only 
vomiting should be documented as AE. 
If vomiting results in severe dehydration, both events should be documented as AEs 
separately. 
10.4.1.3.2 
Abnormal laboratory results and vital signs values 
Not every laboratory or vital signs abnormality needs to be documented as AE. For 
clinically significant laboratory/vital signs abnormalities the following definitions and 
documentation rules apply: 
• If a laboratory/vital signs abnormality is a sign of a disease or syndrome, the 
laboratory/vital signs abnormality is clinically significant and only the diagnosis of 
the causing disease or syndrome needs to be documented as AE. 
• If a laboratory/vital signs abnormality results in specific symptoms but no diagnosis 
of a disease or syndrome can be made, the laboratory/vital signs abnormality is 
clinically significant and only the symptoms need to be documented as AEs. 
• If a laboratory/vital signs abnormality is not a sign of a disease or syndrome and 
does not result in specific symptoms but leads to a change in trial treatment or in a 
medical intervention, the laboratory/vital signs abnormality is clinically significant 
and must be documented as AE. 
10.4.1.3.3 
AEs associated with an overdose or error in drug administration 
An overdose is the accidental or intentional use of a drug in an amount (per administration 
or cumulatively) higher than the dose being studied (for the trial treatment) or higher than 
the maximum recommended dose according to the authorized product information (for 
approved concomitant medications). 
An error in drug administration is any administration outside what is foreseen in the 
protocol (higher or lower), including misuse and abuse of the product. 
An overdose or incorrect administration of a drug is not itself an AE, but it may result in an 
AE. 
All AEs associated with an overdose or incorrect administration of a drug should be 
documented as AE in source data and CRF and reported as SAE if applicable. 
As of issue of protocol version 5.0, all cases of overdose or incorrect administration of a 
drug with or without AEs must be captured as AEs in the CRF as follows: 
• If without an associated AE, as non-serious, related, Grade 1 AEs. 
• If with an associated AE, as related with seriousness and grade corresponding to 
the associated AE. 
10.4.1.4 
Suspected adverse reactions 
Suspected adverse reactions are untoward and unintended responses to an IMP related to 
any dose administered. 
The definition covers also medication errors and uses outside what is foreseen in the 
protocol, including misuse and abuse of the product. 

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The definition implies a reasonable possibility of a causal relationship between the event 
and the IMP. This means that there are facts (evidence) or arguments to suggest a causal 
relationship. 
10.4.2 
Definition of SAEs 
An SAE is defined as any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the trial 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization: 
• In general, hospitalization signifies that the trial subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
• Results in persistent disability/incapacity: 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
• Is a congenital anomaly or birth defect. 
• Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the trial subject or may require medical or surgical treatment to prevent 
one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
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10.4.2.1 
Use of the terms “severe” and “serious” 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an 
AE (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE); see 
Section 10.4.2.2 for guidance on the assessment of severity; the event itself may be of 
relatively minor medical significance (such as severe headache without any further 
findings). Severity and seriousness need to be assessed independently for each AE 
recorded on the CRF. 
SAEs must be reported by the investigator to the sponsor within 24 h after learning of the 
event; see Section 10.4.4 for reporting instructions. 
10.4.2.2 
SAE exemptions 
In general, SAEs are defined according to ICH Topic E2A (CPMP/ICH/377/95), 
EU Directive 2001/20/EC and ENTR/CT-3 (see Section 10.4.2). In the present trial, some 
events are excluded from the SAE definition. The following events do not need to be 
reported as SAEs: 
• AEs and SAEs occurring after the end of the observation period must only be 
reported by the investigator to the sponsor if a relationship to trial treatment or trial 
procedure is suspected. 
• Hospitalizations that were necessary solely because of trial subject requirement for 
care outside of normal outpatient clinic operating hours will not be considered as 
reportable SAE. 
• This trial will allow enrollment of healthy volunteers with pre-existing stable disease. 
Hospitalizations for procedures or interventions of a pre-existing condition of the 
trial subject (elective surgery = planned, non-emergency surgical procedure) will 
not be considered as a reportable SAE (unless the intervention/procedure is 
caused by an acute worsening of the pre-existing condition during the time trial 
participation): 
o if it was planned and documented in trial subject record before the trial-
specific trial subject informed consent was signed (ICF for trial participation, 
see Section 10.1.3), or 
o if it was scheduled during the trial when elective surgery became necessary, 
and the trial subject has not experienced an AE. 
o if it is routine treatment or monitoring of an underlying disease not associated 
with any deterioration in the trial subject’s condition.) 
10.4.3 
Recording and follow-up of AEs and/or SAEs 
AE and SAE recording 
The investigator needs to assess and document any AE regardless of association with the 
use of the trial treatment during the period of observation (see Section 8.3.1). 
• Data pertaining to AEs will be collected during each trial visit. Based on the trial 
subject’s spontaneous description or investigator’s inquiry or discovered in the 
course of examinations done during the visit, clinical significance of any sign or 
symptom needs to be evaluated by the investigator. For the handling of 
reactogenicity reported by the trial subjects, see Section 8.2.5.1. 

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• Clinically significant findings need to be documented as AEs in the source data and 
CRF. Findings that are evaluated and documented in the source data as not 
clinically significant (e.g., an abnormal laboratory value without any clinical 
manifestation), should not be documented as an AE unless reactogenicity events 
that were not recorded into the e-diary due to technical or compliance issues. 
• 
The investigator will then record all relevant AE information in the CRF and 
perform an assessment on: 
o Severity (see the next section “Assessment of severity”) 
o Seriousness 
o Outcome 
o Causal relationship of the AE to the trial treatment/trial procedure 
o Any trial treatment action and/or any other action taken 
• All assessments as well as AE term (diagnosis/description), start date and time of 
onset, end date and time need to be documented in the CRF. 
• There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all trial subject identifiers, with the exception 
of the subject number, will be redacted on the copies of the medical records before 
submission to the sponsor. 
• To avoid colloquial expressions, the AE should be reported in standard medical 
terminology. The investigator will attempt to establish a diagnosis of the event 
based on signs, symptoms, and/or other clinical information. Whenever possible, 
the diagnosis (not the individual signs/symptoms) will be documented as the AE. If 
a definitive diagnosis is not possible, the individual signs and symptoms should be 
recorded. 
Assessment of severity 
The assessment of AE and/or SAE intensity should be done consistently for all trial 
subjects treated with the same treatment and dose. In case of doubt, the trial Medical 
Monitor should be consulted. 
The intensity of (serious) AEs will be graded by the investigator. For further guidance refer 
to the US FDA “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials”. Where specific guidance for an AE term is 
not provided, the following general approach should be followed: 
• Grade 1 - Mild; does not interfere with the trial subject’s usual function. 
• Grade 2 - Moderate; interferes to some extent with the trial subject’s usual function. 
• Grade 3 - Severe; interferes significantly with the trial subject’s usual function. 
• Grade 4 - Potentially life-threatening; life-threatening consequences, urgent 
intervention required. 
With regards the intensity of an (serious) AE, the following needs to be documented and 
CRF: 
• Initial intensity of the AE 

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• For each change of intensity: 
• New grade of intensity 
• Date of change (= start of new grade of intensity) 
• Time of change (only if relevant) 
• New action taken 
A change of severity only needs to be documented if there is a clearly definable change in 
grading of the AE (e.g., a laboratory result changes from severe to moderate). 
An event is defined as “serious” when it meets at least one of the predefined seriousness 
criteria as described in the definition of an SAE, independent from its intensity. 
Actions taken by the investigator 
Actions taken by the investigator as a result of an AE must be documented. 
Action(s) taken with trial treatment (IMPs) by the investigator: 
• Dose not changed (= continuation of trial treatment administration according to the 
trial protocol) 
• Dose reduced (= reduction of the trial treatment dosage *) 
• Drug interrupted (i.e., trial treatment withdrawn temporarily, interruption and 
resumption); i.e.: 
o Drug withdrawn (i.e., trial treatment permanently withdrawn) 
• Unknown (e.g., in case the trial subject is lost to follow-up) 
• Not applicable (e.g., in case treatment with trial treatment has not yet started or 
event starts after last trial treatment administration) 
* If an increase of trial treatment dosage is intended according to the trial protocol and 
the dosage is kept in comparison to last administration of trial treatment, it needs to be 
documented as “Dose reduced.” 
Other action(s) that may be taken by the investigator include: 
• None 
• Initiation of a remedial (concomitant) therapy 
Investigator assessment of the outcome of an AE 
The investigator has to assess the outcome of an AE (and not the trial subject’s outcome) 
at the time of documentation based on the following criteria: 
• Recovered/resolved* (= complete resolution of the AE) 
• Recovering/resolving (= AEs which are improving but not yet resolved completely, 
e.g., decreases in severity grade) 
• Not recovered/not resolved (= AEs which are ongoing without improving or still 
present when the trial subject deceases due to another cause) 

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• Recovered/resolved with sequelae * (= trial subject recuperated but retained 
pathological conditions resulting from the AE; the sequelae should be indicated) 
• Fatal ** (= death due to the AE) 
• Unknown (e.g., in case the trial subject is lost to follow-up) 
* Generally, an AE is defined as recovered/resolved if all symptoms have ceased, no 
medication for treatment of the event is taken anymore and no other measures (e.g., 
hospitalization) are ongoing. 
If the trial subject has developed permanent or chronic symptoms or if the event requires 
long term medication(s), the AE is defined as recovered/resolved with sequelae as soon 
as no changes of symptoms and/or medication(s) are expected anymore. 
An AE that is documented as a worsening of a medical condition already known at 
baseline, is defined as recovered as soon as the medical condition has returned to 
baseline status. 
** In case of a fatal event, the event term should not be “death” but the underlying 
event which led to death (death = outcome). If there is more than one AE in a fatal 
case, only the AE leading to death will be attributed with the outcome “fatal”. All other 
AEs ongoing at the time of death will be attributed with the outcome “not recovered/not 
resolved”. A copy of an autopsy report should be submitted if available. 
Assessment of causality 
The investigator is obligated to assess the relationship between each occurrence of each 
SAE and trial treatment and/or trial procedure. 
The investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial treatment administration 
will be considered and investigated. 
It is sufficient to document the causality in the source data and CRF as: 
• Related (= there is a reasonable possibility of a causal relationship) or 
• Not related (= there is no reasonable possibility of a causal relationship) 
The relationship or association of an AE or SAE to a trial treatment/trial procedure will be 
assessed by the investigator after having evaluated all accessible data and, if necessary, 
he/she will re-evaluate the case as new information becomes available. 
Events caused by the procedure of trial treatment administration should be differentiated 
from events caused by the trial treatment itself. Only events suspected to be caused by the 
IMPs itself should be documented as suspected adverse reactions but not events caused 
by the procedure of trial treatment administration. 
In this trial, it cannot be excluded that during the course of the trial some procedures give 
rise to AEs which are related to the trial procedure and not to the trial treatment. 
Procedure-related AEs occur during or after trial-specific procedure (e.g., discomfort after 
blood drawing) must be reported in the CRF on AE pages as “related to trial procedure” 
with the causing procedure specified. These procedure-related AEs should not include 

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events which correspond to solicited local reactions captured by subject e-diaries (these 
reactions, see Section 8.2.5.1). 
Notes applicable for relationship to trial procedures including trial treatments 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that 
the investigator always makes an assessment of causality for every event before the initial 
transmission of the SAE data to the sponsor. 
The investigator may change their opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
10.4.4 
Reporting of SAEs 
All SAEs (defined in Section 10.4.2) which occur in a trial subject during the observation 
period, whether considered to be associated with trial medication or not, must be reported 
by the investigator to the sponsor within 24 h following first knowledge of the event. 
All SAEs occurring after the end of the period of observation only have to be reported to 
the sponsor if the investigator suspects a relationship to trial medication or the trial 
procedure. 
SAE reporting to the sponsor using paper report forms 
The investigator must ensure the respective paper report form is completed and 
transmitted to the sponsor via one of the following reporting lines: 
• Safety Report Fax No.:   
 
+49 (0) 6131 908
• Safety Report E-Mail address:  
Information for the final description and evaluation of a case report may not be available 
within the required time frames for reporting. Nevertheless, for regulatory purposes, initial 
reports should be submitted if the following minimal information is available: 
• An identifiable trial subject (subject number) 
• A suspected medicinal product 
• An identifiable reporting source (investigator/trial site identification) 
• An event or outcome that can be identified as serious 
For SAEs follow-up information should be sent to the sponsor (indicating that this is a 
“follow-up” report using the respective SAE Form or the Additional Information and Follow-
Up Form) within 24 h after the site becoming aware of the update as described above and 
accompanied by appropriate anonymous supporting documentation (e.g., discharge 
letters, medical reports or death certificates), until a final outcome and date are available. 
All confidential information (name, address, full date of birth) needs to be blackened before 
sending. 
For SAEs, in addition to a medical record, the investigator should complete an Additional 
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A copy of the submitted SAE report must be retained on file by the investigator. If explicitly 
required according to national legislation, the investigator must submit copies of the SAEs 
to the IRB/IEC or authority and retain documentation of these submissions in the Site Trial 
File. 
In case an investigator or any other trial team member has questions on safety reporting 
the sponsor may be contacted via: 
• E-Mail:
For medical questions, the trial Medical Monitor for this trial should be contacted. 
10.4.5 
Assessment of laboratory abnormalities 
Laboratory abnormalities will be graded according to the US FDA “Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials”. 
10.5 
Contraceptive guidance and collection of pregnancy information 
The following definitions and guidance is based on the Clinical Trial Facilitation Group 
(CTFG) recommendations related to contraception and pregnancy testing in clinical trials 
issued in 2020 (CTFG 2020). 
10.5.1 
Definitions 
Volunteer of childbearing potential 
A trial subject born female is considered of childbearing potential, i.e., fertile, following 
menarche and until becoming postmenopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. Documentation for sterilization can come from the trial site personnel’s 
review of the trial subject’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the subject’s medical 
record for the trial. 
For trial subjects with permanent infertility due to a medical cause (e.g., mullerian 
agenesis, androgen insensitivity), investigator discretion should be applied to determine 
trial entry. 
Postmenopausal female 
For the purpose of this document, a postmenopausal state is defined as no menses for 
12 months without an alternative medical cause (verified by high FSH levels). 
A high FSH level in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with more than one 
FSH measurement is required. 
Females on HRT whose menopausal status is in doubt will be required to use one of the 
non-estrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the trial. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before trial enrollment. 

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Fertile men 
For the purpose of this document, a man is considered fertile after puberty unless 
permanently sterile by bilateral vasectomy or orchidectomy. 
10.5.2 
Contraception guidance 
The following guidance describe what is considered highly effective methods of 
contraception. 
The investigator or delegate should advise the trial subject how to achieve highly effective 
contraception. 
The following birth control methods that can achieve a failure rate of less than 1% per year 
when used consistently and correctly may be considered as highly effective: 
• Combined estrogen and progestogen-based hormonal contraception associated 
with inhibition of ovulation 1, i.e., established use of (oral, intravaginal, or 
transdermal) hormonal methods of contraception. 
• Progesterone-only based contraception associated with inhibition of ovulation 1, i.e., 
established use of (oral, injected, or implanted) hormonal methods of 
contraception. 2 
• Intrauterine device. 2 
• Intrauterine hormone-releasing system. 2 
• Bilateral tubal occlusion. 2, 5 
• Bilateral vasectomy (for a male trial subject or male partner of a female trial 
subject). 2, 3 
• Sexual abstinence. 4 
1 
Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2 
Contraception methods that in the context of this guidance are considered to have low user dependency. 
3 
A vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the VOCBP trial subject and that the vasectomized partner has received medical assessment of the surgical 
success. 
4 
In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the trial treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the trial subject. 
5 
Includes bilateral tubal ligation. 
 
10.5.3 
Collection of pregnancy information 
Pregnancy information will only be collected after obtaining written informed consent from 
the pregnant female trial subject (or if a male trial subject’s partner becomes pregnant, 
written informed consent from both). 
The initial and follow-up information must be documented on the paper-based Pregnancy 
Reporting Form and submitted to the sponsor within 24 h of learning of a trial subject’s 
pregnancy/partner’s pregnancy and in the CRF. The completed form needs to be sent to 
the Safety Report Fax number or E-Mail given in Section 10.4.4. Completed pregnancy 
forms must be signed by an investigator before faxing/mailing them to the sponsor. Blank 

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reporting forms are provided to the investigator during the site initiation visit and are filed in 
the ISF. 
The investigator will collect follow-up information on the trial subject/trial subject’s partner 
and the child (at least two times, i.e., at the time of expected date of delivery and around 
the time of the child’s first birthday), and the information will be forwarded to the sponsor. 
Pregnancy follow-up should describe the outcome of the pregnancy, including any 
voluntary or spontaneous termination, details of the birth, the presence or absence of any 
congenital abnormalities, birth defects, maternal or newborn complications and their 
presumed relation to the IMP. 
Pregnancy per se is not an AE (and hence not an SAE). Abnormal pregnancy outcomes 
(e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic 
pregnancy) are considered SAEs. 
Any post-trial pregnancy-related SAE considered reasonably related to the trial treatment 
by the investigator will be reported to the sponsor. While the investigator is not obligated to 
actively seek this information in former trial subjects, the investigator may learn of an SAE 
through spontaneous reporting. 
10.6 
Liver safety: Suggested actions and follow-up assessments 
Not applicable. 
10.7 
Standard definitions 
10.7.1 
Trial site start/closure and trial discontinuation 
The date of first site open (first act of recruitment of potential trial subjects for this trial) is 
the “trial start date”. 
The date when all trial sites are closed is the “date of trial closure”. 
A trial site is considered closed when all required documents and trial supplies have been 
collected and a trial site closure visit has been performed. 
All trial sites will be closed upon trial completion. 
The investigator may initiate trial site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended trial site closure. 
The sponsor reserves the right to close a trial site early or to terminate the whole trial or to 
suspend the whole trial (a temporary halt; an unplanned interruption of the conduct of a 
trial by the sponsor with the intention to resume it) at any time for any reason. 
Reasons for the sponsor to close a trial site early may include but are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of trial subjects by the investigator 
Reasons for the sponsor to suspend the whole trial may include but are not limited to: 
• When there are safety concerns (e.g., if there is an IRC recommendation) 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
Tri al n u m b er: B N T 1 6 2 -2 1  
P a g e 1 0 2  of 1 1 8  
V er si o n: 8. 0  
D at e: 1 6 S E P 2 0 2 4  
 
 
F D A. R e c o m m e n d ati o n f or t h e 2 0 2 3 -2 0 2 4 F or m ul a of C O VI D -1 9 v a c ci n e s i n t h e U. S ., 
1 5   J un  2 0 2 3. A c c e s s e d 1 0  A u g  2 0 2 3 at w w w.f d a. g o v/ m e di a/ 1 6 9 5 9 1/ d o w nl o a d.  
L e B ert N, T a n A T, K u n a s e g ar a n K, et al. S A R S -C o V -2 -s p e cifi c T  c ell i m m u nit y i n c a s e s of 
C O VI D -1 9  a n d S A R S, a n d u ni nf e ct e d c o ntr ol s. N at ur e. 2 0 2 0; 5 8 4( 7 8 2 1): 4 5 7 -4 6 2. 
d oi: 1 0. 1 0 3 8/ s 4 1 5 8 6 -0 2 0 -2 5 5 0 -z . 
M ui k A, L ui B G, W alli s c h A -K, et al. N e utr ali z ati o n of S A R S -C o V -2  O mi cr o n b y B N T 1 6 2 b 2 
m R N A v a c ci n e -eli cit e d h u m a n s er a. S ci e n c e. 2 0 2 2; 3 7 5( 6 5 8 1): 6 7 8 -6 8 0. 
d oi: 1 0. 1 1 2 6/ s ci e n c e. a b n 7 5 9 1.  
N ati o n al H e art, L u n g, a n d Bl o o d I n stit ut e G ui d a n c e  2 0 0 7. E x p ert P a n el R e p ort  3: 
G ui d eli n e s f or t h e Di a g n o si s a n d M a n a g e m e nt of A st h m a  (i n cl u di n g t h e 2 0 2 0 F o c u s e d 
U p d at e s t o t h e A st h m a M a n a g e m e nt G ui d eli n e s: A R e p ort fr o m t h e N ati o n al A st h m a 
E d u c ati o n a n d Pr e v e nti o n Pr o gr a m C o or di n ati n g C o m mitt e e E x p ert P a n el W or ki n g 
Gr o u p ). 
N g O -W, C hi a A, T a n A T, et al. M e m or y T  c ell r e s p o n s e s t ar g eti n g t h e S A R S c or o n a vir u s 
p er si st u p t o 1 1 y e ar s p o st -i nf e cti o n. V a c ci n e. 2 0 1 6; 3 4( 1 7): 2 0 0 8-1 4. 
d oi: 1 0. 1 0 1 6/j. v a c ci n e. 2 0 1 6. 0 2. 0 6 3.  
P ol a c k F P, T h o m a s S J, Kit c hi n N, et al. S af et y a n d Effi c a c y of t h e B N T 1 6 2 b 2 m R N A 
C o vi d -1 9 V a c ci n e. N E n gl J M e d. 2 0 2 0; 3 8 3( 2 7): 2 6 0 3 -2 6 1 5. d oi: 1 0. 1 0 5 6/ N E J M o a 2 0 3 4 5 7 7.  
P or a n A, H arj a nt o D, M all o y M, et al. S e q u e n c e -b a s e d pr e di cti o n of S A R S -C o V -2  v a c ci n e 
t ar g et s u si n g a m a s s s p e ctr o m etr y-b a s e d bi oi nf or m ati c s pr e di ct or i d e ntifi e s i m m u n o g e ni c 
T  c ell e pit o p e s. G e n o m e M e d 2 0 2 0; 1 2( 1): 7 0. htt p s:// d oi. or g/ 1 0. 1 1 8 6/ s 1 3 0 7 3 -0 2 0 -0 0 7 6 7 -w . 
C CI
C CI
C CI

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
Tri al n u m b er: B N T 1 6 2 -2 1  
P a g e 1 0 3  of 1 1 8  
V er si o n: 8. 0  
D at e: 1 6 S E P 2 0 2 4  
 
 
W H O C or o n a vir u s [ C O VI D -1 9 ] D a s h b o ar d, a c c e s s e d 1 0 A U G  2 0 2 2 at htt p s:// w w w. w h o.i nt.  
W H O  St at e m e nt o n t h e a nti g e n c o m p o siti o n of C O VI D -1 9 v a c ci n e s, 1 8   Ma y  2 0 2 3. 
A c c e s s e d o n 1 0  A u g  2 0 2 3 at w w w. w h o.i nt/ n e w s/it e m/ 1 8 -0 5 -2 0 2 3 -st at e m e nt -o n -t h e-
a nti g e n -c o m p o siti o n -of -c o vi d -1 9 -v a c ci n e s.  
Z h a n g Z, M at e u s J, C o el h o C H, et al. H u m or al a n d c ell ul ar i m m u n e m e m or y t o f o ur 
C O VI D -1 9 v a c ci n e s. C ell. 2 0 2 2; 1 8 5( 1 4): 2 4 3 4 -2 4 5 1. e 1 7. d oi: 1 0. 1 0 1 6/j. c ell. 2 0 2 2. 0 5. 0 2 2 . 
S p o n s or cli ni c al tri al B N T 1 6 2 -0 1. A m ulti -sit e, P h a s e  I/II, 2-p art, d o s e e s c al ati o n tri al 
i n v e sti g ati n g t h e s af et y a n d i m m u n o g e ni cit y of f o ur pr o p h yl a cti c S A R S -C o V -2  R N A 
v a c ci n e s a g ai n st C O VI D -1 9  u si n g diff er e nt d o si n g r e gi m e n s i n h e alt h y a n d 
i m m u n o c o m pr o mi s e d a d ult s. Cli ni c al Tri al s. g o v I d e ntifi er: N C T 0 4 3 8 0 7 0 1. 
S p o n s or cli ni c al tri al C 4 5 9 1 0 3 1. A P h a s e  3 m a st er pr ot o c ol t o e v al u at e a d diti o n al d o s e( s) 
of B N T 1 6 2 b 2 i n h e alt h y i n di vi d u al s pr e vi o u sl y v a c ci n at e d wit h B N T 1 6 2 b 2. 
Cli ni c al Tri al s. g o v I d e ntifi er: N C T 0 4 9 5 5 6 2 6.  
S p o n s or cli ni c al tri al C 4 5 9 1 0 4 4. A n i nt er v e nti o n al, r a n d o mi z e d, a cti v e-c o ntr oll e d, P h a s e  2 
o b s er v er -bli n d st u d y t o i n v e sti g at e t h e s af et y, t ol er a bilit y, a n d i m m u n o g e ni cit y of a bi v al e nt 
B N T 1 6 2 b -b a s e d v a c ci n e c a n di d at e a s a b o o st er d o s e i n C O VI D -1 9  v a c ci n e  e x p eri e n c e d 
h e alt h y a d ult s . Cli ni c al Tri al s. g o v I d e ntifi er: N C T 0 5 4 7 2 0 3 8 . 
1 2  
A D V E R S E R E A C TI O N  M A N A G E M E N T  
1 2. 1  
M a n a g e m e nt of l o c al a n d s y st e mi c r e a ct o g e ni cit y e v e nt s  
T h e a d v er s e r e a cti o n s d et er mi n e d f or B N T 1 6 2 b 2 fr o m t h e a v ail a bl e u n bli n d e d cli ni c al tri al 
d at a (fr o m B N T 1 6 2 -0 2 / C 4 5 9 1 0 0 1) ar e m o stl y r efl e cti v e of mil d t o m o d er at e l o c al a n d 
s y st e mi c r e a ct o g e ni cit y e v e nt s. T h e m o st fr e q u e nt a d v er s e r e a cti o n s i n tri al s u bj e ct s 
1 6  yr s of a g e a n d ol d er w er e i nj e cti o n sit e p ai n, f ati g u e, h e a d a c h e, m y al gi a a n d c hill s, 
art hr al gi a, p yr e xi a a n d i nj e cti o n sit e s w elli n g, a n d w er e u s u all y mil d or m o d er at e i n 
i nt e n sit y a n d r e s ol v e d wit hi n 1 t o 3  d aft er B N T 1 6 2 b 2 a d mi ni str ati o n . A d ditio n al a d v er s e 
r e a cti o n s d et er mi n e d fr o m t h e cli ni c al tri al d at a ar e l y m p h a d e n o p at h y, n a u s e a a n d 
m al ai s e. Si n c e a ut h ori z ati o n of B N T 1 6 2 b 2, a n a p h yl a xi s h a s b e e n r e p ort e d a n d d et er mi n e d 
t o b e a n a d v er s e r e a cti o n. F or d et ail s s e e t h e B N T 1 6 2  I B. 
Tr e at m e nt of t h e s e e v e nt s i s at t h e di s cr eti o n of t h e i n v e sti g at or s; h o w e v er, t h e f oll o wi n g 
m a n a g e m e nt s u g g e sti o n s ar e pr o vi d e d:  
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• After the first occurrence of flu-like symptomatology including fever, subjects can be 
treated with standard therapeutic dose of acetaminophen (preferable), or a non-
steroidal anti-inflammatory drug if acetaminophen is contraindicated, according to 
local guidance after the immunization. 
• Corticosteroids should be avoided as either prophylaxis or treatment as it 
counteracts the effects of immunization. 
If subjects experience enhanced respiratory disease or progression of flu-like 
symptomatology, such as non-resolution of the symptoms after 3 d, symptom kinetics that 
are inconsistent with a relationship to RNA immunization, additional diagnostic measures 
should be considered, and the trial Medical Monitor should be informed. 
12.2 
Management of symptoms that could represent myocarditis or 
pericarditis 
If any trial subjects report symptoms that could represent myocarditis or pericarditis, 
please follow the US CDC Clinical Considerations for myocarditis and pericarditis following 
COVID-19 (https://www.cdc.gov/vaccines/covid-19/clinical-
considerations/myocarditis.html) which includes but not limits following: 
• Consider myocarditis and pericarditis in persons with acute chest pain, shortness of 
breath, or palpitations. 
• For suspected cases, consider consultation with cardiologists for assistance with 
cardiac evaluation and management. Evaluation and management may vary 
depending on the patient age, clinical presentation, potential causes, or practice 
preference of the provider. 
• For follow-up of patients with myocarditis, consult the guidance from the American 
Heart Association and American College of Cardiology. 
• It is important to rule out other potential causes of myocarditis and pericarditis. 
Consider consultation with infectious disease and/or rheumatology to assist in this 
evaluation. 
Where available, evaluate for potential causes of myocarditis and pericarditis, particularly 
acute COVID-19 infection (such as PCR testing), current or prior SARS-CoV-2 infection 
(such as, detection of SARS-CoV-2 antibodies), and other viral causes (such as, 
enterovirus PCR and comprehensive respiratory viral pathogen testing). 
12.3 
Management of risks associated with anemia 
This trial limits the total volume drawn over each sequential 8-week period to less than 
550 mL, however, if a trial subject develops anemia, they should be evaluated and treated 
with iron supplements if appropriate. 
If the trial subject develops Grade 3 anemia, the volume of blood drawn at any visit will be 
kept to a minimum, i.e., may be reduced to only safety assessments, at the discretion of 
the investigator. 

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12.4 
Management of risks linked to the pandemic COVID-19 
Risks linked to the pandemic COVID-19 will be managed by requiring: 
• Avoidance of contact with persons tested positive for SARS-CoV-2. 
• Practice of social distancing and follow good practices to reduce their chances of 
being infected or spreading COVID-19 during their participation in the trial. 
• Completion of health status checks which include symptom-directed physical 
examinations, vital signs assessments, and clinical laboratory tests as planned in 
the SoAs (see Section 1.3 and Section 13.5). 
• Assessments planned at the predefined “Potential COVID-19 Illness Visit”. 
Subjects will be asked 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. 
13 
COHORT 5 SPECIFIC INFORMATION 
13.1 
Summary – Cohort 5 
See Section 1.1 for a synopsis of the overall trial. 
See Figure 4 for a schema depicting Cohort 5. 
See Section 13.5 for the SoA for Cohort 5. 
13.2 
Introduction – Cohort 5 
13.2.1 
Background 
See Section 2 for an introduction including trial background. 
13.2.2 
Rationale 
Cohort 5 will investigate the safety, reactogenicity, and immunogenicity of two doses of 
30 µg BNT162b4 alone in healthy subjects aged 18 to 55 yrs. See Section 2.2 for the trial 
rationale. 
13.2.3 
Benefit/risk assessment 
No additional risks are anticipated for Cohort 5 beyond those described in Section 2.3. The 
benefit-risk balance is assessed as positive for BNT162b4 administered as monotherapy. 
13.3 
Trial design – Cohort 5 
13.3.1 
Planned number of trial subjects 
See Table 2 for the planned number of trial subjects. 

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13.3.2 
Trial duration 
The planned trial duration for each trial subject in Cohort 5 who receives two doses of IMP 
is up to ~6 months (up to ~1 month [28 d] screening and ~3 months follow-up after Dose 2 
of IMP). 
13.4 
Trial assessments and procedures – Cohort 5 
For assessments and procedures, see Section 8. 
 

Bi o N T e c h S E  
C o nfi d e nti al  
Cli ni c al Tri al Pr ot o c ol  
Tri al n u m b er: B N T 1 6 2 -2 1  
P a g e 1 1 1  of 1 1 8  
V er si o n: 8. 0  
D at e: 1 6 S E P 2 0 2 4  
 
 
N ot e s  
T h e t ot al bl o o d v ol u m e dr a w n o v er a n y 8 -w e e k p eri o d i n a n y c o h ort will al w a y s b e l e s s t h a n 5 5 0  m L. A d diti o n al bl o o d s a m pl e s m a y b e t a k e n, e. g., f or s af et y a s s e s s m e nt s aft er 
A E s or S A E s. A s s u mi n g t h er e ar e n o u n pl a n n e d vi sit s, t h e t ot al v ol u m e of bl o o d dr a w n fr o m e a c h s u bj e ct d uri n g tri al p arti ci p ati o n will b e u p t o ~ 8 5 0  m L.  
 
A b br e vi ati o n s : A E = a d v er s e e v e nt;
 C O VI D-1 9 = c or o n a vir u s di s e a s e 2 0 1 9; d  =  d a y( s); D  =  d o s e; E arl y t er m.  =  e arl y t er mi n ati o n ( vi sit); 
E C G  =  el e ctr o c ar di o gr a m; F U = f oll o w -u p ( vi sit); h  =  h o ur( s); β -H C G = b et a h u m a n c h ori o ni c g o n a d otr o pi n;
 I M P = i n v e sti g ati o n al m e di ci n al 
pr o d u ct; m = m o nt h( s); N A A T = n u cl ei c a ci d a m plifi c ati o n -b a s e d t e st; N/ A = n ot a p pli c a bl e; S A E = s eri o u s a d v er s e e v e nt; S A R S -C o V -2 = s e v er e a c ut e r e s pir at or y s y n dr o m e 
c or o n a vir u s  2; V O C B P  =  v ol u nt e er s of c hil d b e ari n g p ot e nti al.  
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7 
Have been vaccinated with at least three doses of an RNA-based COVID-19 
vaccine authorized in the US before Visit 0. The last COVID-19 RNA vaccine dose 
must have been administered at least 90 d before Visit 1. 
Note: Documented confirmation of prior COVID-19 vaccine receipt must be 
obtained prior to Visit 1. 
Virology 
8 
Have negative human immunodeficiency virus (HIV)-1 and HIV-2 test results at 
Visit 0. 
9 
Have negative Hepatitis B surface antigen (HBsAg) test results at Visit 0. 
10 
Have negative anti-Hepatitis C virus (HCV) antibodies, or negative HCV 
polymerase chain reaction (PCR) test results if the anti-HCV is positive at Visit 0. 
Reproductive status and contraception 
11 
Volunteers of childbearing potential (VOCBP) that have a negative serum β-HCG 
pregnancy test result at Visit 0 and negative urine pregnancy test results prior to 
receiving Dose 1 and a negative urine pregnancy test result prior to receiving 
Dose 2. Volunteers born female that are postmenopausal or permanently sterilized 
(verified by medical records) will not be considered VOCBP (for definitions of 
postmenopausal or permanently sterilized, see Section 10.5). 
12 
VOCBP who agree to practice a highly effective form of contraception (for guidance 
on contraception, see Section 10.5) and to require their male sexual partners to 
use condoms with a spermicidal agent, starting at Visit 0 and continuously until 
28 d after receiving the last IMP dose. 
13 
VOCBP who agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during trial, starting at Visit 0 and continuously until 28 d after 
receiving the last IMP dose. 
14 
Men who are sexually active with partners of childbearing potential and who have 
not had a verified vasectomy (documented in medical records) that agree to use 
condoms with a spermicidal agent and to practice a highly effective form of 
contraception with their sexual partners born female (for guidance on 
contraception, see Section 10.5) starting at Visit 0 and continuously until 28 d after 
receiving the last IMP dose. 
15 
Men who are willing to refrain from sperm donation, starting at Visit 0 and 
continuously until 28 d after receiving the last IMP dose. 
 

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13.7.2 
Exclusion criteria – Cohort 5 
Volunteers are not eligible to be included in the trial if any of the following criteria apply: 
1 
Breastfeeding or intending to become pregnant starting with Visit 0 until 28 d after 
receiving the last dose of trial IMP or intending to father children starting with Visit 0 
until 28 d after receiving the last trial IMP dose. 
2 
History of any severe adverse reactions to vaccines or to vaccine components and 
including history of anaphylaxis and related symptoms such as hives, respiratory 
difficulty, angioedema, and/or abdominal pain. (Not excluded from participation: a 
volunteer who had an anaphylactic adverse reaction to pertussis vaccine as a 
child). 
3 
Current or history of the following medical conditions: 
a) Uncontrolled or moderate or severe respiratory diseases (e.g., asthma, 
chronic obstructive pulmonary disease); symptoms of asthma severity as 
defined in the most recent US National Heart, Lung, and Blood Institute 
asthma management guidelines - e.g., exclude a volunteer who: 
o Uses a short-acting rescue inhaler (typically a beta 2 agonist) 
daily, or 
o Uses high dose inhaled corticosteroids (per National Heart, Lung, 
and Blood Institute asthma management guidelines [Tables 4–
8b]), or 
o In the past year has either of the following: 
▪ Greater than one exacerbation of symptoms treated with 
oral/parenteral corticosteroids; 
▪ Needed emergency care, urgent care, hospitalization, or 
intubation for asthma. 
b) Diabetes mellitus type 1 or type 2, or new onset of Diabetes mellitus 
type 1 or 2 from the administration of Dose 1, including cases controlled 
with diet alone (Not excluded: history of isolated gestational diabetes). 
c) Hypertension: 
▪ 
If a person has been found to have elevated blood pressure or 
hypertension during screening or previously, exclude for “blood 
pressure that is not well controlled”. Well controlled blood pressure is 
defined as consistently ≤140 mm Hg systolic and ≤90 mm Hg 
diastolic, with or without medication, with only isolated, brief 
instances of higher readings, which must be ≤150 mm Hg systolic 
and ≤90 mm Hg diastolic at Visit 0. 

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▪ 
If a person does not have a history of elevated blood pressure or 
hypertension previously or during screening, also exclude for systolic 
blood pressure ≥150 mm Hg at Visit 0 or diastolic blood pressure 
≥100 mm Hg at Visit 0. 
Subjects who have new onset of worsening hypertension since 
enrollment that, in the opinion of the investigator, would constitute an 
increased risk to the subject’s participation in Dose 2 will not receive 
Dose 2. 
d) Any current or history of cardiovascular diseases such as myocarditis, 
pericarditis, myocardial infarction, symptomatic congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias. 
Subjects who have new onset of cardiovascular disease since 
enrollment that, in the opinion of the investigator, would constitute an 
increased risk to the subject’s participation in Dose 2 will not receive 
Dose 2. 
e) A diagnosed bleeding disorder (e.g., factor deficiency, coagulopathy, or 
platelet disorder requiring special precautions). 
Subjects who have new onset of a bleeding disorder since enrollment 
that, in the opinion of the investigator, would constitute an increased risk 
to the subject’s participation in Dose 2 will not receive Dose 2. 
f) Seizure disorders: History of seizure(s) within the past 3 yrs. Also 
exclude if volunteer has used medications in order to prevent or treat 
seizure(s) at any time within the past 3 yrs. 
g) Screening 12-lead ECG that is consistent with probable or possible 
myocarditis or pericarditis or demonstrates clinically relevant 
abnormalities that may affect subject safety or interpretation of the trial 
results. 
Only symptomatic subjects or whose clinical picture, in the opinion of the 
investigator, warrant ECG will have a repeat 12-lead ECG. 
Note for exclusion criteria 3g: ECG changes including but not limited to: 
paroxysmal or sustained atrial or ventricular arrhythmias, atrioventricular 
(AV) block (grade 2-3) or bundle branch block, diffuse ST-segment 
elevation or PR-segment inversion, QTcF interval (QT interval corrected 
by the Fridericia formula) >450 ms in men and >460 ms in women, 
changes supporting myocardial infarction and/or myocardial ischemia. 
Subjects who have a repeat ECG prior to Dose 2 and have a change or 
new onset that in the opinion of the investigator should not receive 
Dose 2, will not receive Dose 2. 
4 
Current or history of major psychiatric illness, including but not limited to bipolar 
disorder, major depressive disorder, schizophrenia, autism, and attention deficit-

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hyperactivity disorder that could interfere with participation and follow-up as 
required by the trial protocol. 
5 
Current or history of the following diseases associated with immune dysregulation: 
• Primary immunodeficiencies. 
• History of solid organ or bone marrow transplantation. 
• Asplenia: any condition resulting in the absence of a functional spleen. 
• Currently existing or history of autoimmune disease including and not 
limited to thyroid autoimmune disease, multiple sclerosis, or psoriasis. 
Prior/concomitant therapy 
6 
Received any non-trial IMP within 28 d before Dose 1 and Dose 2 (except seasonal 
influenza vaccine, which should be given at least 14 d before or after any 
administration of IMP). 
7 
Received or planned treatment throughout the entire trial with radiotherapy or 
immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids 
(if systemic corticosteroids are administered for ≥14 d at a dose of ≥20 mg/d of 
prednisone or equivalent), e.g., for cancer or an autoimmune disease, or planned 
receipt throughout this trial. Inhaled/nebulized (except high doses as per exclusion 
criteria 3a), intraarticular, intrabursal, or topical (skin or eyes) corticosteroids are 
permitted. 
8 
Blood/plasma products and/or immunoglobulin containing therapy (including 
monoclonal antibodies) received within 120 d before dosing or administration is 
planned starting at Visit 0 or prior to Dose 2 until 90 d after the last IMP 
administration in this trial. 
9 
Received allergy treatment with antigen injections within 28 d before dosing or 
where allergy treatment with antigen injections are scheduled within 14 d after any 
visit with IMP administration in this trial. 
10 
Subjects with a history of SARS-CoV-2 infection (symptomatic or asymptomatic) 
<60 d prior to Visit 1. 
11 
Have received any non-RNA or unauthorized COVID-19 vaccine, aside from 
Dose 1 of the current trial. 
Additional exclusions 
12 
Any existing condition which may affect IMP administration and/or assessment of 
local reactions assessment at the injection site, e.g., tattoos, severe scars, etc. 
13 
Are vulnerable individuals as per ICH E6 definition, i.e., are individuals whose 
willingness to volunteer in a clinical trial may be unduly influenced by the 
expectation, whether justified or not, of benefits associated with participation, or of 

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a retaliatory response from senior members of a hierarchy in case of refusal to 
participate. 
14 
Any screening hematology and/or blood chemistry laboratory value that meets the 
definition of a Grade ≥1 abnormality at Visit 0, or an abnormal C-reactive protein 
(identified by any method) or troponin I value. 
Note: Volunteers with any stable Grade 1 abnormalities (according to the toxicity 
grading scale) may be considered eligible at the discretion of the investigator. 
(Note: “stable” Grade 1 laboratory abnormality is defined as a report of Grade 1 on 
an initial blood sample that remains ≤ Grade 1 upon repeat testing on a second 
sample from the same volunteer). 
Gilberts disease, in and of itself, is not considered exclusionary. 
Only symptomatic subjects or whose clinical picture, in the opinion of the 
investigator, warrant laboratory investigation will have a repeat lab(s). 
15 
History of alcohol abuse or drug addiction within 1 yr before Visit 0, or a history 
(within the past 5 yrs) of substance abuse or known medical, psychological, or 
social conditions which, in the opinion of the investigator, could compromise their 
wellbeing if they participate as subjects in the trial, or that could prevent, limit, or 
confound the protocol-specified assessments. 
 
13.8 
Trial treatments – Cohort 5 
For trial treatments, see Section 6.1. 
13.9 
Statistical considerations – Cohort 5 
For statistical considerations, see Section 9.