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BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
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PHARMACOVIGILANCE PLAN FOR
BIOLOGIC LICENSE APPLICATION #125742
OF
COMIRNATY® ( PFIZER -BIONTECH COVID -19 Vaccine VACCINE , mRNA,
BNT162b2, PF -07302048 )
Date of Report: 26 August 15 December 2021
Version 1.24
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TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ..................... 3
LIST OF FIGURES ................................ ................................ ................................ ................... 6
LIST OF ABBREVIATIONS ................................ ................................ ................................ ....7
1. INTRODUCTION ................................ ................................ ................................ ............... 10
1.1. Product Details ................................ ................................ ................................ ........ 10
2. SAFETY SPECIFICATION ................................ ................................ ................................ 12
2.1. Elements of the Safety Specification ................................ ................................ .......12
2.1.1. Non-Clinical ................................ ................................ ............................... 12
2.1.2. Clinical ................................ ................................ ................................ ........ 15
2.1.2.a. Limitations of the Human Safety Database ............................... 15
2.1.2.b. Populations Not Studied in the Pre -Approval Phase ................. 58
2.1.2.c. Adverse Events / Ad verse Reactions ................................ ......... 60
2.1.2.d. Identified and Potential Interactions, Including Food -
Biologic Product and Drug -Biologic Product Interact ions ............... 77
2.1.2.e. Epidemiology of Indication and Target Population .................. 77
2.1.2 f. Pharmacological Class Effects ................................ ................... 96
3. PHARMACOVIGILANCE PLAN ................................ ................................ ...................... 96
3.1. Structure of the Pharmacovigilance Plan ................................ ................................ 96
3.1.1. Summary of Ongoing Safety Concerns ................................ ...................... 96
3.1.2. Routine Pharmacovigilance Practices ................................ ......................... 97
3.1.3. Action Plan for Safety Issues ................................ ................................ ......99
3.1.4. Summary of Actions to be Completed, Including Milestones .................. 119
3.2. Pharmacovigilance Methods ................................ ................................ ................. 134
3.2.1. List of Studies Included in the Pharmacovigilance Plan .......................... 134
REFERENCES ................................ ................................ ................................ ...................... 135
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LIST OF TABLES
Table 1. Product Details ................................ ................................ .......................... 10
Table 2. Key Safety Findings and Relevance to Human Usage ............................. 14
Table 3. Exposure to BNT162b2 by Age Group and Dose (C4591001) –
Blinded Placebo -Controlled Follow -up Period ................................ ........ 22
Table 4. Exposure to BNT162b2 by Age Group and Dose (C4591001) –
Open -Label Follow -up Period – Subjects Who Originally Received
BNT162b2 ................................ ................................ ................................ 23
Table 5. Exposure to BNT162b2 by Age Group and Dose (C4591001) –
Open -Label Follow -up Period – Subjects Who Originally Received
Placebo and Then Received BNT162b2 After Unblinding ...................... 24
Table 6. Exposure to BNT162b2 by Age Group and Dose (BNT162 -01) ............. 25
Table 7. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Blinded
Placebo -Controlled Follow -up Period ................................ ...................... 28
Table 8. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Open -
Label Follow -up Period – Subjects Who Originally Received
BNT162b2 ................................ ................................ ................................ 28
Table 9. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Open -
Label Follow -up Period – Subjects Who Originally Received
Placebo and Then Received BNT162b2 After Unblinding ...................... 28
Table 10. Exposure to BNT162b2 by Dose (Totals) (BNT162 -01) ......................... 29
Table 11. Exposure to BNT162b2 by Dose, Age Group, and Gender
(C4591001) – Blinded Placebo -Controlled Follow -up Period ................. 30
Table 12. Exposure to BNT162b2 by Dose, Age Group, and Gender
(C4591001) – Open -Label Follow -up Period – Subjects Who
Originally Received BNT162b2 ................................ ............................... 31
Table 13. Exposure to BNT162b2 by Dose, Age Group, and Gender
(C4591001) – Open -Label Follow -up Period – Subjects Who
Originally Received Placebo and Then Received BNT162b2 Aft er
Unblinding ................................ ................................ ................................ 31
Table 14. Exposure to BNT162b2 by Dose, Age Group, and Gender
(BNT162 -01) ................................ ................................ ............................ 32
Table 15. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethn ic
Origin (C4591001) – Blinded Placebo -Controlled Follow -up Period ......33
Table 16. Exposure to BNT162b2 by Age Group, Dose, and Race/Et hnic
Origin (C4591001) – Open -Label Follow -up Period – Subjects
Who Originally Received BNT162b2 ................................ ...................... 37
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Table 17. Exposure to BNT162b2 b y Age Group, Dose, and Race/Ethnic
Origin (C4591001) – Open -Label Follow -up Period – Subjects
Who Originally Received Placebo and Then Received BNT162b2
After Unblinding ................................ ................................ ....................... 39
Table 18. Exposure to BNT162b2 by Dose and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period ................. 41
Table 19. Exposure to BNT162b2 by Dose and Race/Ethnic Origin
(C4591001) – Open -Label Follow -up Period – Subjects Who
Originally Received BNT162b2 ................................ ............................... 43
Table 20. Exposure to BNT162b2 by Dose and Race/Ethnic Origin
(C4591001) – Open -Label Follow -up Period – Subjects Who
Originally Received Placebo and Then Received BN T162b2 After
Unblinding ................................ ................................ ................................ 43
Table 21. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (BNT162 -
01) ................................ ................................ ................................ ............. 44
Table 22. Exposure to BNT162b2 (30 μg) by Special Population (C4591001)
– Blinded Placebo -Controlled Follow -up Period ................................ .....45
Table 23. Exposure to BNT162b2 (30 μg) by Special Population (C4591001)
– Open -Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding ......46
Table 24. Exposure to BNT162b2 by Dose (Totals) (C4591001) – 12-15
Years – Blinded Placebo -Controlled Follow -up Period ........................... 47
Table 25. Exposure to BNT162b2 by Dose (Totals) (C4591001) – 12-15
Years – Open -Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding ......48
Table 26. Exposure to BNT162b2 by Gender (C4591001) – 12-15 Years –
Blinded Placebo -Controlled Follow -up Period ................................ ........ 49
Table 27. Exposure to BNT162b2 by Gender (C4591001) – 12-15 Years –
Open-Label Follow -up Period – Subjects Who Originally Received
Placebo and Then Received BNT162b2 After Unblinding ...................... 49
Table 28. Exposu re to BNT162b2 by Race/Ethnic Origin (C4591001) – 12-15
Years – Blinded Placebo -Controlled Follow -up Period ........................... 50
Table 29. Exposure to BNT162b2 by Race/Ethnic Origin (C4591001) – 12-15
Years – Open -Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding ......51
Table 30. Exposure to BNT162b2 (30 μg) by Special Population (C4591001)
– 12-15 Years – Blinded Placebo -Controlled Follow -up Period .............. 52
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Table 31. Exposure to BNT162b2 (30 μg) by Special Population (C4591001)
– 12-15 Years – Open -Label Follow -up Period – Subjects Who
Originally Received Place bo and Then Received BNT162b2 After
Unblinding ................................ ................................ ................................ 53
Table 32. Cumulative Estimated Shipped/Administered Doses of BNT162b2
by Region Wo rldwide ................................ ................................ ............... 56
Table 33. Exposure of Special Populations Included or not in Clinical Trial
Development Programs ................................ ................................ ............ 58
Table 34. Myocarditis and Pericarditis ................................ ................................ .....61
Table 35. Anaphylaxis ................................ ................................ .............................. 66
Table 36. Vaccine -Associated Enhance d Disease (VAED), including
Vaccine -Associated Enhanced Respiratory Disease (VAERD) ............... 68
Table 37. Use in Pregnancy and Lactation ................................ ............................... 72
Table 38. Vaccine Effectiveness ................................ ................................ ............... 74
Table 39. Use in Paediatric Individuals <5 Years of Age§ ................................ .......76
Table 40. Incidence, Prevalence, and Mortality of COVID -19 as of 15 August
202115 ................................ ................................ ................................ ........ 78
Table 41. Distribution of Cases (n=29,346,352) b y Age, Sex, Race, and
Cross -Tabulated Age and Sex -- United States as of 14 August
2021 22 ................................ ................................ ................................ .......82
Table 42. Distribution of Deaths (n=513,204) by Age, Sex, Race, and
Cross -Tabulated Age and Sex -- United States as of 14 August
2021 22 ................................ ................................ ................................ .......82
Table 43. COVID -19 incidence and rate ratios, by age group among persons
aged <25 years across three periods of 2020 in 16 U.S.
jurisdictions36 ................................ ................................ ............................ 85
Table 44. Demographics of 135,794 US individuals under age 25 tested for
COVID -19 by 08 September 202037 ................................ ......................... 86
Table 45. Risk for COVID -19 infection, Hospitalisation, and Death by Age
Group and by Race/Ethnicity47 ................................ ................................ .87
Table 46. Hazard Ratios and 95% Confidence Intervals for COVID -19-related
Death57 ................................ ................................ ................................ ......88
Table 47. Signs and symptoms among 291 pediatric (age <18 years) and
10,944 adult (age 18 –64 years) patients with laboratory confirmed
COVID -19 — United States, 12 February – 2April 2020 73 ..................... 91
Table 48. Preconditions among COVID -19 Patients in EU/EEA, by Severity
of Disease. Case -based Data from TESSy Reported 12 August
2021110 ................................ ................................ ................................ ......94
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Table 49. Comorbidities in individuals tested for COVID -19 in the
Providence St. Joseph Health System – States of California,
Oregon, and Washington, 01 March –31 December 2020 51 ..................... 95
Table 50. Ongoing Safety Concerns ................................ ................................ ......... 96
Table 51. Action Plan for Important Identified Risk “ Myocarditis and
Pericarditis” ................................ ................................ .............................. 99
Table 52. Action Plan for Important Identified Risk “ Anaphylaxis” ..................... 103
Table 53. Action Plan for Important Potential Risk “ Vaccine -associated
enhanced disease (VAED) including Vaccine -associated enhanced
respiratory disease (VAERD)” ................................ ............................... 106
Table 54. Action Plan for Missing Information “Use in Pregnancy and
Lactation” ................................ ................................ ............................... 109
Table 55. Action Plan for Missing Information “ Vaccine Effectiveness ” ............. 112
Table 56. Action Plan for Missing Information “Use in Paediatric Individuals
<5 Years of Age” ................................ ................................ .................... 113
Table 57. Summary of Saf ety Concerns and Action Plans ................................ .....120
LIST OF FIGURES
Figure 1. Age-Sex distribution of COVID -19 Cases as Different Levels of
Severity, Pooled Data for EU/EEA Countries. Case -based Data
from TESSy produced on 12 August 2021a ................................ .............. 80
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LIST OF ABBREVIATIONS
Abbreviation Definition of Term
AE adverse event
AESI adverse event of special interest
A:G albumin:globulin
ALC -0315 ((4-hydroxybutyl)azanediyl)bis(hexane -6,1-diyl)bis (2-
hexyldecanoate )
ALC -0159 2-[(polyethylene glycol) -2000] -N,N-
ditetradecylacetamide
ARDS acute respiratory distress syndrome
BALB/c bagg albino
BC Brighton Collaboration
BEST biologics effectiveness and safety
BLA biologics license application
BMI body mass index
BP blood pressure
CD4, CD8 cluster of differentiation -4, 8
CDC Centers for Disease Control and Prevention
CI confidence interval
COPD chronic obstructive pulmonary disease
COVID -19 coronavirus disease 2019
CSR clinical study report
CT clinical trial
DART developmental and reproductive toxicology
DCA data capture aid
DLP data-lock point
DoD Department of Defense
ECDC European Center for Disease Control
EEA European Economic Area
EMA European Medicines Agency
eGFR estimated glomerular filtration rate
EU European Union
EUA emergency use authorization
FDA (US) Food and Drug Administration
GLP good laboratory practice
HbA1c glycated hemoglobin
HBV hepatitis b virus
HCV hepatitis c virus
HIV human immunodeficiency virus
IA interim analysis
ICU intensive care unit
IFN interferon Interferon
IL-4 interleukin -4
IM intramuscular(ly)
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Abbreviation Definition of Term
IMD index of multiple deprivation
IND investigational new drug
LNP lipid nanoparticle
LOE lack of efficacy
MAAMAH marketing authorization applicant holder
MedDRA Medical Dictionary for Regulatory Activities
MERS -CoV Middle East respiratory syndrome –coronavirus
MHS Military Health System
MIS-C multisystem inflammatory syndrome in children
MOA mechanism of action
modRNA nucleoside -modified messenger ribonucleic acid
mRNA messenger ribonucleic acid
NCMD National child mortality database
NDA new drug application
NDS new drug submission
NHP nonhuman primate
NHS National Health Service
NICE National Institute for Health and Care Excellence
OCS oral corticosteroids
OTIS Organization of Teratology Information Specialists
PHN Pediatric Heart Network
PK pharmacokinetic
PRAC pharmacovigilance risk assessment committee
PT Preferred Term
PVP pharmacovigilance plan
RBC red blood cell
RMP Risk Management Plan
RNA ribonucleic acid
RR relative risk
RSV respiratory syncytial virus
SAE serious adverse event
SARS severe acute respiratory syndrome
SARS -CoV -1 severe acute respiratory syndrome coronavirus 1
SARS -CoV -2 severe acute respiratory syndrome coronavirus 2
siRNA small -interfering RNA
SMQ SMSR standardised MedDRA query summary monthly safety
report
Tdap tetanus, diphtheria, and acellular pertussis
TESSy The European Surveillance System
Th1 T helper cell type 1
Th2 T helper cell type 2
UK United Kingdom
US United States
USP United States pharmacopeia
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Abbreviation Definition of Term
V8 variant 8
V9 variant 9
VAED vaccine -associated enhanced disease
VAERD vaccine -associated enhanced respiratory disease
WBC white blood cells
WHO World Health Organization
WOCBP women of childbearing potential
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1. INTRODUCTION
1.1. Product Details
Table 1. Product Detailsa
Product COVID -19 Vaccine , mRNA, herein after r eferred to as BNT162b2 is a
nucleoside -modified messenger RNA –((modRNA ) encoding the viral spike
(S) glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS -
CoV -2).
Brief description of the
product Chemical class:
Nucleoside -modRNA formu lated in lipid particles .
Mechanism of Action :
The modRNA in the BNT162b2 is formulated in lipid particles, which enable
delivery of the RNA mRNA into host cells to allow expression of the SARS -
CoV -2 S antigen. The vaccine elicits an immune response to the S antigen,
which protects against COVID -19.
Important information about its composition :
• The BNT162b2 is a sterile suspension for injection.
• The BNT162b2 is supplied as a frozen suspension in multiple dose vials .
• Each vial must be diluted with 1.8 mL of sterile 0.9% Sodium Chloride
Injection, USP prior to use to form the vaccine.
• Each dose of the BNT162 b2 contains 30 mcg of a nucleoside -modified
messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of
SARS -CoV -2.
• Each 0.3 mL dose of the BNT162b2 also includes the following
ingredients:
lipids (0.43 mg (((4-hydroxybutyl)azanediyl)bis(hexane -6,1-diyl)bis(2 -
hexyldecanoate), 0.05 mg 2 [(-(polyethylene glycol )-2000 ]-)-N,N-
ditetradecylacetamide, 0.09 mg 1,2 -distearoyl -sn-glycero -3-
phosphocholine, and 0.2 mg cholesterol), 0.01 mg potassium chloride,
0.01 mg monobasic potassium phosphate, 0.36 mg sodium chloride,
0.07 mg dibasic sodium phosphate dihydrate, and 6 mg sucrose. The
diluent (0.9% Sodium Chloride Injection, USP) contributes an additional
2.16 mg sodium chloride per dose.
• The BNT162b2 does not contai n preservative.
• The vial stoppers are not made with natural rubber latex.
Indication Current : Active immunization to prevent COVID -19 caused by SARS -CoV -2
in individuals 16 years of age and older.
Proposed : Active immunization to prevent COVID -19 caused b y SAR S-CoV -
2 in individuals 12 years of age and older .
Dosage and route of
administration Proposed :
A primary Current :
BNT162b2 is administered intramuscularly as a series of two doses (0 3 mL
each) 3 weeks apart , intramuscular ly.
A booster dose (a third dose) may be administered intramuscularly
approximately 6 months after the second dose .There are no data available on
the interchangeability of BNT162b2 with other COVID -19 vaccines to
complete the vaccination series. Individuals who have received 1 dose of
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2. SAFETY SPECIFICATION
2.1. Elements of the Safety Specification
2.1.1. Non-Clinical
Nonclinical evaluation of BNT162b2 included pharmacology (mouse immunogenicity and
NHP immunogenicity and challenge studies), pharmacokinetic (series of biodistribution,
metabolism and pharmacokinetic studies), and toxicity (2 GLP rat repeat -dose toxicity and a
GLP DART) studies in vitro a nd in vivo. No additional toxicity studies are planned for
BNT162b2 .
Nonclinical studies in mice and NHP for BNT162b2 demonstrated both a strong neutralizing
antibody response and a Th1 -type CD4+ and an IFN + CD8+ T-cell response. The Th1
profile is characterized by a strong IFNγ, but not IL -4, response indicating the absence of a
potentially deleterious Th2 immune response and is a pattern favored for vaccine safety and
efficacy.1 Rhesus macaques (Study VR -VRT -10671) that had received two IM
immunizations with 100 µg BNT162b2 or saline 21 days apart were challenged with 1.05 ×
106 plaque forming units of SARS -CoV -2 (strain USA -WA1/2020), split equally between the
intranasal and intratracheal routes.2 BNT162b2 provided complete protection from the
presence of detectable viral RNA in the lungs compared to the saline control with no clinical,
radiological or histopathological evidence of vaccine -elicited disease enhancement.
An intravenous rat PK study, using an LNP with the identical lipid composition as
BNT162b2 , demonstrated that the novel lipid excipients in the LNP formulation, ALC -0315
and ALC -0159, distribute from the plasma to the liver. While there was no detectable
excretion of either lipid in the urin e, the percent of dose excreted unchanged in feces was
~1% for ALC -0315 and ~50% for ALC -0159. Further studies indicated metabolism played a
role in the elimination of ALC -0315. Biodistribution was assessed using luciferase
expression as a surrogate repo rter formulated like BNT162b2 , with the identical lipid
composition. After IM injection of the LNP -formulated RNA encoding luciferase in
BALB/c mice, luciferase protein expression was demonstrated at the site of injection 6 hours
post dose and expression decreased over time to almost reach background levels after 9 days.
Luciferase was detected to a lesser extent in the liver; expression was present at 6 hours after
injection and was not detected by 48 hours after injection. After IM administration of a
radiolabeled LNP -mRNA formulation containing ALC -0315 and ALC -0159 to rats, the
percent of administered dose was also greatest at the injection site. Outside of the injection
site, total recovery of radioactivity was greatest in the liver and much lower in the spleen,
with very little recovery in the adrenal glands and ovaries. The metabolism of ALC -0315
and ALC -0159 was evaluated in blood, liver microsomes, S9 fractions, and hepatocytes from
mice, rats, monkeys, and humans. The in vivo metabolism was exa mined in rat plasma,
urine, feces, and liver samples from the PK study. ALC -0315 and ALC -0159 are
metabolized by hydrolytic metabolism of the ester and amide functionalities, respectively,
and this hydrolytic metabolism is observed across the species eval uated.
In GLP toxicity studies, two variants of the BNT162b2 candidate were tested, designated
“variant 8” and “variant 9” (V8 and V9, respectively). The variants differ only in their codon
optimization sequences which are designed to improve antigen expr ession, otherwise the
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amino acid sequences of the encoded antigens are identical. BNT162b2 (V9) was evaluated
clinically and submitted for application. Two GLP -compliant repeat -dose toxicity studies
were performed in Wistar Han rats; one with each varian t. Both studies were 17 days in
duration with a 3 -week recovery period. A GLP -compliant DART study in Wistar Han rats
has also been completed. Safety pharmacology, genotoxicity and carcinogenicity studies
have not been conducted, in accordance with the 2005 WHO vaccine guideline.3
The IM route of exposure was selected for nonclinical investigation s as it is the clinical route
of administration. Rats were selected as the toxicology test species as they demonstrated an
antigen -specific immune response to the vaccine and are routinely used for regulatory
toxicity studies with an extensive historical safety database.
Administration of up to 100 µg BNT162b2 by IM injection to male and female Wistar Han
rats once every week, for a total of 3 doses, was tolera ted without evidence of systemic
toxicity. Expected inflammatory responses to the vaccine were evident such as edema and
erythema at the injection sites, transient elevation in body temperature, elevations in WBC
count and acute phase reactants, and lower A:G ratios. Injection site reactions were common
in all vaccine -administered animals and were greater after boost immunizations. Changes
secondary to inflammation included slight and transient reduction in body weights and
transient reduction in reticul ocytes, platelets and RBC mass parameters. Decreased
reticulocytes were reported in rats treated with the licensed LNP -siRNA pharmaceutical
Onpattro™ (NDA # 210922) but have not been observed in humans treated with this
biotherapeutic4 suggesting this i s a species -specific effect. Decreased platelet counts were
noted after repeat administration, but were small in magnitude of change, likely related to
inflammation -related platelet activation and consumption, and unassociated with other
alterations in he mostasis. Elevated levels of gamma -glutamyl transferase were observed in
the first repeat -dose toxicity study with BNT162b2 (V8) without evidence of cholestasis or
hepatobiliary injury but was not recapitulated in the second repeat dose -toxicity study with
BNT162b2 (V9), the final clinical candidate. All changes in clinical pathology parameters
and acute phase proteins were rever sed at the end of the recovery phase for BNT162b2 , with
the exception of low magnitude higher red cell distribution width (consistent with a
regenerative erythroid response) and lower A:G ratios (resulting from acute phase response)
in animals administered BNT162b2 . Macroscopic pathology and organ weight changes were
also consistent with immune activation and inflammatory response and included increased
size and/or weight of draining iliac lymph nodes and spleen. Vaccine -related microscopic
findings at th e end of the dosing phase consisted of edema and inflammation in injection sites
and surrounding tissues, increased cellularity in the draining iliac lymph nodes, bone marrow
and spleen and hepatocyte vacuolation in the liver. Vacuolation of periportal he patocytes,
the only test article -related liver microscopic finding, was not associated with any
microscopic evidence of hepatic injury or hepatic functional effects (i.e., liver functional
enzymes were not elevated) and may be associated with hepatocyte up take of the LNP
lipids.5 Microscopic findings at the end of the dosing phase were partially or completely
recovered in all animals at the end of the 3 -week recovery period for BNT162b2 . A robust
immune response was elicited to the BNT162b2 antigen.
Admin istration of BNT162b2 to female rats twice before the start of mating and twice during
gestation at the human clinical dose (30 µg) was associated with non -adverse effects (body
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weight, food consumption and effects localized to the injection site) after ea ch dose
administration. However, there were no effects of BNT162b2 administration on mating
performance, fertility, or any ovarian or uterine parameters in the F0 female rats nor on
embryo -fetal or postnatal survival, growth, or development in the F1 offsp ring. An immune
response was confirmed in F0 female rats following administration of each vaccine candidate
and these responses were also detectable in the F1 offspring (fetuses and pups).
In summary, the nonclinical safety findings related to BNT162b2 administration primarily
represent an expected immune reaction to vaccine administration and are clinically
manageable or acceptable risks in the intended population. The key safety findings regarding
BNT162b2 from nonclinical studies and their relevance to human usage are presented in
Table 2. There was no evidence of vaccine -elicited disease enhancement.
Table 2. Key Safety Findings and Relevance to Human Usage
Key Safety findings from Nonclinical Studiesa Relevance to Human Usage
Pharmacology
NHP Challenge Model
• No evidence of vaccine -elicited disease
enhancement.
• Suggests low risk of vaccine -enhanced disease
in humans; being investigated in CTs.
Toxicity
Injection site reactions:
• Injection site reactions were common and
reversible or showed signs of reversibility at the
end of the 3 -week recovery period in nonclinical
studies.
• In common with other vaccines, BNT162b2
administration has the potential to generate
injection site reac tions such as edema and
erythema at the injection sites.
Inflammation and immune activation:
• Evidence of inflammation or immune activation
was common, reversible, and included transiently
higher body temperature, higher circulating
WBCs, and higher acute phase reactants.
Secondarily, transiently lower body weights,
reticulocytes, platelets, and RBC mass parameters
were observed.
• In common with all vaccines, BNT162b2
administration has the potential to generate
inflammation which can lead to increased
body temperature, higher circulating WBCs
and higher acute phase proteins.
• Decreased reticulocytes have not been
observed in humans treated with the
LNP -siRNA pharmaceut ical Onpattro4,
suggesting this finding in rats is a species -
specific effect.
• BNT162b2 administration has the potential to
transiently decrease p latelets and RBC mass
parameters. These slight decreases are not
likely to be clinically meaningful due to their
small magnitude.
Developmental and Reproductive Toxicity
• No vaccine -related effects on female fertility or the
development of fetuses or offspring were observed
in a DART study of BNT162b2 in rats.
• No effects are anticipated in WOCBP,
pregnant women or their offspring.
a. Safety pharmacology, genotoxicity, and carcinogenicity studies were not conducted, in accordance with
2005 WHO vaccine guideline, as they are generally not considered necessary to support dev elopment and
licensure of vaccines for infectious diseases.3 In addition, the components of the vaccine construct are lipids
and RNA and are not expected to have carcinogenic or genotoxic potential.
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2.1.2. Clinical
2.1.2.a. Limitations of the Human Safety Database
The pivotal study was initially planned to enroll approximately 30,000 participants, which
would have a probability of 78% of detecting an AE with a frequency of 0.01% (1/1000) and
a probability of 95% of detecting an AE with a frequency of 0.02% (1/500). The protocol
was amended to enroll approximately 46,000 participants, which would slightly enhance the
ability to detect AEs. However, rarer events might not be detected.
Participants in the pivotal study were initially planned to be followed for up to 24 months in
order to assess the potential for late -occurring adverse reactions, such as the theoretical risk
of VAED. After completing the final efficacy analysis with vaccine efficacy shown to be
95%, and obtaining regulatory authorization to vaccinate in many countries,
Pfizer -BioNTech started to unblind all participants to determine those randomized to placebo
so that they could be offered vaccine in accordance with local authorizatio n. To date, most
placebo subjects have been unblinded to receive active vaccine at or prior to 6 months after
the second dose, therefore, a placebo group for comparison of safety data is only available
for up to 6 months post Dose 2.
2.1.2.a.1. Clinical Trial Exposu re
Brief Overview of Development
Study BNT162 -01
BioNTech is conduct ing a first -in-human dose level –finding Phase 1/2 study (BNT162 01) in
Germany to gather safety and immunogenicity data to enable evaluation of 4 vaccines
candidates individually to inform the overall clinical development of a BNT162b2 .
BNT162 -01 is not conducted under the US IND application but is being conducted under a
German Clin ical Trial Application.
Four vaccine candidates were evaluated in Study BNT162 -01. Based on safety and
immunogenicity results from this study, 2 vaccine candidates, BNT162b1 and BNT162b2,
were selected for evaluation in Study C4591001, which is a Phase 1 /2/3 randomized,
placebo -controlled, observer -blind, dose -finding, vaccine candidate -selection, and efficacy
study in healthy adults (conducted under IND 019736).
Phase 1 of Study C4591001
➢ Phase 1: comprised dose -level –finding evaluations of the 2 selected vaccine candidates;
multiple dose levels (some corresponding to those evaluated in Study BNT162 -01) were
evaluated. Study vaccine was administered using the same 2 -dose schedule as in Study
BNT162 -01 (21 days apart). Dose levels were administered first to an 18 - to 55 -year age
cohort, then to a 65 - to 85 -year age cohort.
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Both vaccine candidate constructs were safe and well tolerated. BNT162b2 at the 30-µg
dose level was selected and advanced to the Phase 2/3 expanded cohort and efficacy
evaluation prima rily because:
• the reactogenicity profile for BNT162b2 was more favorable than BNT162b1 in both
younger and older adults with similar immunogenicity results;
• in the NHP challenge study (VR -VTR -10671 , see Section 2.1.1 Section 2.1.1 ), a trend
toward earlier clearance of BNT162b2 was observed in the nose.
➢ Phase 2 of the study (for which (enrollment has completed) comprised the evaluation of
safety and immunogenicity data for the first 360 participants (180 from the active vaccine
group and 180 from the placebo group , with each group divided between the younger and
older age cohorts) enteri ng the study after completion of Phase 1.
➢ The Phase 3 part of the study (which is ongoing) evaluates the efficacy and safety in all
participants (including the first 360 participants from Phase 2). Phase 3 introduced :
• enrol lment of participants 16 to 17 y ears of age to be evaluated with the 18 - to 55 -
year-old cohort,
• enrollment of a 12- to 15-year-old coh ort,
• immunogenicity data from the 12- to 15-year-old cohort (
Table 3. Exposure to BNT162b2 by Age Group and Dose (C4591001) – Blinded
Placebo -Controlled Follow -up Period
• , Table 5, Table 11, Table 13, Table 15, and Table 17), anticipated to bridge to the 16-
to 25-year-old cohort.
• Booster groups were subsequently added to evaluate boostability and protection
against variant virus strains.
Participants in the pivotal study were initially planned to be followed for up to 24 months in
order to assess the potential for late -occurring adverse reactions, such as the theoretical r isk
of VAED including VAERD . After completing the final efficacy analysis with vaccine
efficacy shown to be 95% and obtaining regulatory authori zation to vaccinate in many
countries, Pfizer -BioNTech started to unblind all participants to determine those pa rticipants
randomised to placebo so that they could be offered vaccine in accordance with local
authori zation. To date, most placebo subjects have been unblinded to receive active vaccine
at or prior to 6 months after the second dose, therefore, a placebo group for comparison of
safety data is only available for up to 6 months post Dose 2.
The initial efficacy analysis on the 16 years and older population was event -driven, with
prespecified interim analyses after accrual of at least 62, 92, and 120 cases and a final
analysis at 164 cases.
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A further efficacy analysis has been conducted on 12- to ≤15 -year-old cohort participants and
on 16 years and older participants cohort participants reported by 13 March 2021.
For evaluation of booster effects and/or protection against emerging SARS CoV 2 variants
of concern, approximately 600 existing Phase 3 participants 18 to 55 years of age were
randomized 1:1 to receive either receive a booster (Dose 3) at 30 µg of either BNT162b2 or a
prototype based upon the B.1.351 (Beta) variant that originated in South Africa,
BNT162b2 SA, approximately 6 months after their second dose of BNT162b2.
Other o ngoing1 BNT162b2 interventional studies at the cut-off of the clinical database ( 17
June02 Sept ember 2021) also include:
• C4591005: A phase 1/2 study , placebo -controlled, randomized, and observer -blind study
to evaluate the safety, tolerability, and immunogenicity of ana SARS -CoV-2 RNA va ccine
candidate against COVID -19 in healthy Japanese adults.
One hundred sixty participants were randomly assigned in a 3:1 ratio to study
intervention (candidate vaccine: 120, placebo: 40).
• PASS : C4591015: A phase 2/3 study , placebo -controlled, randomized, observer -blind
study to evaluate the safety, tolerability, and immunogenicity of SARS -CoV-2 RNA
vaccine candidate (BNT162b2) against COVID -19 in healthy pregnant women 18 years
of age and older.
Approximately 4000 pregnan t women at 24 to 34 weeks gestation are being randomized
in a 1:1 ratio to vaccine or placebo.
• C4591017: A phase 3 , randomized , observer blind study to evaluate the safety,
tolerability, and immunogenicity of multiple production lots and dose levels of
BNT162b2 against COVID 19 in healthy participants 12 through 50 years of age and
the safety tolerability, and immunogenicity of BNT162b2 RNA based COVID 19
vaccine candidates as a booster dose in healthy participants 18 through 50 years of
age..
Approximately 340 participants were randomly assigned to each of 3 US lots and to a
20μg arm and approximately 170 participants were randomly assigned an EU lot, for
a total of approximately 1530 randomized participants in 5 study arms.
Protocol amendment 2 has added a booster study in which a subset of the adult
participa nts (18 through 50 years of age) who each received two 30 µg doses of the
designated US lot(s) will be randomly assigned to 1 of 2 arms in a 1:1 ratio (Booster
1: Booster 2), where Booster 1 is BNT162b2 at 30 µg and Booster 2 is
BNT162b2.B.1.351 at 30 µg. The third dose will be administered approximately 3
months after BNT162b2 Dose 2 of the primary study.
• C4591007: A phase 1, open -label dose -finding study to evaluate safety, tolerability, and
immunogenicity and phase 2/3 placebo -controlled, observer -blind ed safety, tolerability,
1 Study C4591017 was completed and therefore is removed from this list.
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and immunogenicity study of a SARS -CoV-2 RNA vaccine candidate against COVID -19
in healthy children <12 years of age .
Phase 1 is an open -label dose -finding study that consist s of up to 3 different dos e levels
in each age group, wit h 16 participants per dose level (total of 144 participants). Phase
2/3 will evaluate the safety, tolerability, and immunogenicity of the selected dose level in
each age group from Phase 1, with a total of approximately 4500 participants.
Participants wi ll be randomized in a 2:1 ratio to receive active vaccine or placebo.
• C4591020 : A phase 3, randomized, observer -blind study to evaluate the safety,
tolerability, and immunogenicity of multiple formulations of the vaccine candidate BNT -
162B2 against C OVID -19 in healthy adults 18 through 55 years of age .
• C4591031 A phase 3 master protoc ol to evaluate additional dose(s) of BNT162B2 in
healthy individuals previously vaccinated with BNT162B2 .
• BNT162 -01 A multi -site, phase I/II, 2 -Part, dose -escalation trial investigating the safety
and immunogenicity of four prophylactic SARS -CoV-2 RNA vaccines against COVID -19
using different dosing regimens in healthy and immunocompromised adults.
• BNT162 -032 Safety and immunogenicity of SARS -CoV-2 mRNA vaccine (BNT162b1) in
Chinese healthy subjects: A phase I, randomized, placebo - controlled, observer -blind
study .
• BNT162 -04 A multi -site, phase I/II, 2 -part, dose escalation trial investigating the safety
and immunogenicity of a prophylactic SARS -CoV-2 RNA vaccine (BNT162b3) against
COVID -19 using different dosing regimens in healthy adults .
• BNT162 -062 Safety and immunogenicity of SARS -CoV-2 mRNA vaccine (BNT162b2) in
Chinese healthy population: A phase II, randomized, placebo -controlled, observer -blind
study
• BNT162 -14 A Phase II, open -label, rollover trial to evaluate the safety and
immunogenicity of one or two boosting doses of Comirnaty or one dose of BNT162b2s01
in BNT162 -01 trial subjects, or two boosting doses of Comirnaty in BNT162 -04 trial
subjects
• BNT162 -17 A P hase II trial to evaluate the safety and immunogenicity of a SARS -CoV -2
multivalent RNA vaccine in healthy subjects.
Clinical Trial Exposure
Population for analysis of CTs data in this US Pharmacovigilance Plan includes the
following 2 studies:
2 This study is conducted by Shanghai Fosun Pharmaceutical Development, Inc. and sponsored by
BioNTech SE.
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C4591001: Phase 1/2/3, placebo -controlled, randomized, observer -blind, dose finding, study
to evaluate the safety, tolerability, immunogenicity, and efficacy of SARS -CoV-2 RNA
vaccine candidates against COVID -19 in healthy individuals .
BNT162 -01: A multi -site, phase I/II, 2 -part, dose -escalation trial investigating the safety and
immunogenicity of four prophylactic SARS -CoV-2 RNA vaccines against COVID -19
using different dosing regimens in healthy adults.
Participants 16 years of age and older
At the cut-off date of 13 March 2021, a total of 46,505 participants were vaccinated in the
BNT162b2 clinical development program:
• 21,745 participants received 2 doses and 360 received 1 dose of BNT162b2
during the blinded follow -up period; 96 participants from study BNT162 -01
received 2 doses of the vaccine .
• 19,647 participants , who originally received placebo, then received 1 dose of
BNT162b2 in the Open -Label Follow -up period after unblinding. (none from
study BNT162 -01).
Exposure to BNT162b2 for participants aged 16 years and older in the 2 ongoing studies by
number of doses, and demographic characteristics is shown in
Table 3. Exposure to BNT162b2 by Age Group and Dose (C4591001) – Blinded
Placebo -Controlled Follow -up Period
through Table 21.
In addition, exposure in clinical studies in special populations is provided in Table 22 and
Table 23.
Participants 12 to 15 years of age
• At the cut -off date of 13 March 2021, a total of 2260 participants 12 to 15 years of
age were vaccinated in the BNT162b2 clinical development program : (study
C4591001) .
• Clinical At the cut -off date of 02 September 2021, updated c linical study exposure
data for the 12 - to 15 years of age are provided for the ongoing study C4591001 at the
cutoff date of 13 March 2021. :
In this study
o 1124 One thousand one hundred twenty -four ( 1124 ) participants received 2 doses
and 7 received 1 dose of BNT162b2 in the Blinded -Placebo Controlled Follow -
up period .
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o 49One thousand and ten (1010 ) participants who originally received placebo,
then received 1 dose of BNT162b2 (18) or 2 doses (992) in the Open-Label
Follow -up period after unblinding.
Exposure to BNT162b2 for participants aged 12 - to 15 years of age by number of doses
and demographic characteristics is shown in
Table 3. Exposure to BNT162b2 by Age Group and Dose (C4591001) – Blinded
Placebo -Controlled Follow -up Period
,Table 5, Table 11, Table 13, Table 15, Table 17. (at the cut -off date of 13 March 2021)
and in Table 24, Table 25, Table 26, Table 27, Table 28, and Table 29 (at the cut -off date
of 02 September 2021) . In addition, exposure in clinical studies in special populations is
provided in Table 22 and Table 23Table 23, Table 30 and Table 31.
Booster dose
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Exposure in participants 1812 years of age and older
At the cut (Studies C4591001 – Cut-off date of 17 June 13 March 2021 , a total of 306 participants ,
18 to 55 years of age, received BNT162b2 30 µg as booster dose (Dose 3) ; these participant , were originally
randomized in the Phase 3 study and completed the BNT162b2 (30 µg) two-dose series, and then received a
third dose of BNT162b2 (30 µg) approximately 6 months after receipt of Dose 2, with safety and immune
response evaluations at 1 month after Dose 3. BNT162 -01 – Cut off date 23 October 2020)
Exposure to BNT162b2 for participants who received the booster dose , by number of doses
and demograph ic characteristics , is shown in Table 24 and Table 25. In addition, exposure in
special population who received the booster dose is provided in Table 26.
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Table 3. Exposure to BNT162b2 by Age Group and Dose (C4591001) – Blinded
Placebo -Controlled Follow -up Period
Age Group
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥12 years to ≤15 years
Vaccine 30 µg
1 Dose 7 7
2 Doses 1124 2248
Total 1131 2255
≥16 years to ≤17 years
Vaccine 30 µg
1 Dose 4 4
2 Doses 374 748
Total 378 752
≥18 years to ≤55 years
Vaccine 10 µg
2 Doses 12 24
Total 12 24
Vaccine 20 µg
2 Doses 12 24
Total 12 24
Vaccine 30 µg
1 Dose 267 267
2 Doses 12438 24876
Total 12705 25143
>55 years to ≤64 years
Vaccine 30 µg
1 Dose 67 67
2 Doses 4341 8682
Total 4408 8749
≥65 years to ≤74 years
Vaccine 10 µg
2 Doses 12 24
Total 12 24
Vaccine 20 µg
2 Doses 9 18
Total 9 18
Vaccine 30 µg
1 Dose 17 17
2 Doses 3624 7248
Total 3641 7265
≥75 years to ≤84 years
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Table 3. Exposure to BNT162b2 by Age Group and Dose (C4591001) – Blinded
Placebo -Controlled Follow -up Period
Age Group
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 20 µg
2 Doses 3 6
Total 3 6
Vaccine 30 µg
1 Dose 3 3
2 Doses 899 1798
Total 902 1801
≥85 years
Vaccine 30 µg
1 Dose 2 2
2 Doses 21 42
Total 23 44
Note: 30 μg includes data from phase 1 and phase 2/3.
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Table 4. Exposure to BNT162b2 by Age Group and Dose (C4591001 ) – Open -Label
Follow -up Period – Subjects Who Originally Received BNT162b2
Age Group
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥16 years to ≤17 years
Vaccine 30 µg
1 Dose 3 3
≥18 years to ≤55 years
Vaccine 30 µg
1 Dose 58 58
>55 years to ≤64 years
Vaccine 30 µg
1 Dose 17 17
≥65 years to ≤74 years
Vaccine 30 µg
1 Dose 8 8
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Table 4. Exposure to BNT162b2 by Age Group and Dose (C4591001 ) – Open -Label
Follow -up Period – Subjects Who Originally Received BNT162b2
Age Group
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥75 years to ≤84 years
Vaccine 30 µg
1 Dose 1 1
≥85 years
Vaccine 30 µg
1 Dose 2 2
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Subjects who received 2nd Dose of BNT162b2 after unblinding.
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Table 5. Exposure to BNT162b2 by Age Group and Dose (C4591001) – Open -Label
Follow -up Period – Subjects Who Originally Received Placebo and Then
Received BNT162b2 After Unblinding
Age Group
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥12 years to ≤15 yearsa
Vaccine 30 µg
1 Dose 30 30
2 Doses 19 38
Total 49 68
≥16 years to ≤17 years
Vaccine 30 µg
1 Dose 107 107
2 Doses 186 372
Total 293 479
≥18 years to ≤55 years
Vaccine 30 µg
1 Dose 2713 2713
2 Doses 8419 16838
Total 11132 19551
>55 years to ≤64 years
Vaccine 30 µg
1 Dose 655 655
2 Doses 3330 6660
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Table 5. Exposure to BNT162b2 by Age Group and Dose (C4591001) – Open -Label
Follow -up Period – Subjects Who Originally Received Placebo and Then
Received BNT162b2 After Unblinding
Age Group
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Total 3985 7315
≥65 years to ≤74 years
Vaccine 30 µg
1 Dose 128 128
2 Doses 3286 6572
Total 3414 6700
≥75 years to ≤84 years
Vaccine 30 µg
1 Dose 23 23
2 Doses 783 1566
Total 806 1589
≥85 years
Vaccine 30 µg
1 Dose 1 1
2 Doses 16 32
Total 17 33
Note: 30 μg includes data from phase 1 and phase 2/3.
a. Includes subjects who became eligible for unblinding at 16 years of age, confirmed to have received
placebo originally and then received BNT162b2 post unblinding.
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Table 6. Exposure to BNT162b2 by Age Group and Dose (BNT162 -01)
Age Group
Dose
Exposure (Number of Doses
Received) No. of Subjects
Exposed to BNT162b2 Total No. of Vaccine Doses
≥18 years to ≤ 64 years
Vaccine 1 µg
1 Dose 1 1
2 Doses 11 22
Total 12 23
Vaccine 3 µg
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Table 6. Exposure to BNT162b2 by Age Group and Dose (BNT162 -01)
Age Group
Dose
Exposure (Number of Doses
Received) No. of Subjects
Exposed to BNT162b2 Total No. of Vaccine Doses
1 Dose 0 0
2 Doses 12 24
Total 12 24
Vaccine 10 µg
1 Dose 1 1
2 Doses 11 22
Total 12 23
Vaccine 20 µg
1 Dose 0 0
2 Doses 17 34
Total 17 34
Vaccine 30 µg
1 Dose 0 0
2 Doses 18 36
Total 18 36
≥65 years to ≤74 years
Vaccine 1 µg
1 Dose 0 0
2 Doses 0 0
Total 0 0
Vaccine 3 µg
1 Dose 0 0
2 Doses 0 0
Total 0 0
Vaccine 10 µg
1 Dose 0 0
2 Doses 5 10
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Table 6. Exposure to BNT162b2 by Age Group and Dose (BNT162 -01)
Age Group
Dose
Exposure (Number of Doses
Received) No. of Subjects
Exposed to BNT162b2 Total No. of Vaccine Doses
Total 5 10
Vaccine 20 µg
1 Dose 0 0
2 Doses 6 12
Total 6 12
Vaccine 30 µg
1 Dose 0 0
2 Doses 6 12
Total 6 12
≥75 years to ≤84 years
Vaccine 1 μg
1 Dose 0 0
2 Doses 0 0
Total 0 0
Vaccine 3 μg
1 Dose 0 0
2 Doses 0 0
Total 0 0
Vaccine 10 µg
1 Dose 0 0
2 Doses 1 2
Total 1 2
Vaccine 20 µg
1 Dose 0 0
2 Doses 1 2
Total 1 2
Vaccine 30 µg
1 Dose 0 0
2 Doses 0 0
Total 0 0
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Table 7. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Blinded Placebo -
Controlled Follow -up Period
Dose
Exposure (Number of
Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 10 µg
2 Doses 24 48
Total 24 48
Vaccine 20 µg
2 Doses 24 48
Total 24 48
Vaccine 30 µg
1 Dose 367 367
2 Doses 22821 45642
Total 23188 46009
Note: 30 μg includes data from phase 1 and phase 2/3.
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Table 8. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Open -Label Follow -
up Period – Subjects Who Originally Received BNT162b2
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 30 µg
1 Dose 89 89
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Subjects who received 2nd Dose of BNT162b2 after unblinding.
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Table 9. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Open -Label Follow -
up Period – Subjects Who Originally Receive d Placebo and Then Received
BNT162b2 After Unblinding
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 30 µg
1 Dose 3657 3657
2 Doses 16039 32078
Total 19696 35735
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Table 9. Exposure to BNT162b2 by Dose (Totals) (C4591001) – Open -Label Follow -
up Period – Subjects Who Originally Receive d Placebo and Then Received
BNT162b2 After Unblinding
Dose
Exposure (Number of Doses Received) Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Note: 30 μg includes data from phase 1 and phase 2/3.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:46)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2 unblinded/C4591001 PVP BLA/adsl s9222
Table 10. Exposure to BNT162b2 by Dose (Totals) (BNT162 -01)
Dose
Exposure (Number of Doses Received) No. of Subjects
Exposed to
BNT162b2 Total No. of Vaccine Doses
Vaccine 1 µg
1 Dose 1 1
2 Doses 11 22
Total 12 23
Vaccine 3 µg
1 Dose 0 0
2 Doses 12 24
Total 12 24
Vaccine 10 µg
1 Dose 1 1
2 Doses 23 46
Total 24 47
Vaccine 20 µg
1 Dose 0 0
2 Doses 24 48
Total 24 48
Vaccine 30 µg
1 Dose 0 0
2 Doses 24 48
Total 24 48
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220703
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 30
Table 10. Exposure to BNT162b2 by Dose (Totals) (BNT162 -01)
Dose
Exposure (Number of Doses Received) No. of Subjects
Exposed to
BNT162b2 Total No. of Vaccine Doses
PFIZER CONFIDENTIAL SDTM Creation: 24NOV2020 (15:06) Source Data: adsl Table Generation: 10MAR2021
(11:49) (Cutoff date:23OCT2020, Snapshot Date: 23OCT2020)
Output File: ex_b2_dose rtf
Table 11. Exposure to BNT162b2 by Dose, Age Group, and Gender (C4591001) –
Blinded Placebo -Controlled Follow -up Period
Number of Subjects Exposed
to BNT162b2 Total Number of Vaccine
Doses
Dose
Age Group Male Female Male Female
Vaccine 10 µg
≥18 years to ≤55 years 5 7 10 14
≥65 years to ≤74 years 2 10 4 20
Total 7 17 14 34
Vaccine 20 µg
≥18 years to ≤55 years 6 6 12 12
≥65 years to ≤74 years 4 5 8 10
≥75 years to ≤84 years 1 2 2 4
Total 11 13 22 26
Vaccine 30 µg
≥12 years to ≤15 years 567 564 1128 1127
≥16 years to ≤17 years 187 191 373 379
≥18 years to ≤55 years 6456 6249 12770 12373
>55 years to ≤64 years 2231 2177 4421 4328
≥65 years to ≤74 years 1934 1707 3858 3407
≥75 years to ≤84 years 511 391 1020 781
≥85 years 12 11 23 21
Total 11898 11290 23593 22416
Note: 30 μg includes data from phase 1 and phase 2/3.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:46)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2 unblinded/C4591001 PVP BLA/adsl s932
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220704
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 31
Table 12. Exposure to BNT162b2 by Dose, Age Group, and Gender (C4591001) –
Open -Label Follow -up Period – Subjects Who Originally Received
BNT162b2
Number of Subjects
Exposed to BNT162b2 Total Number of Vaccine
Doses
Dose
Age Group Male Female Male Female
Vaccine 30 µg
≥16 years to ≤17 years 0 3 0 3
≥18 years to ≤55 years 24 34 24 34
>55 years to ≤64 years 12 5 12 5
≥65 years to ≤74 years 4 4 4 4
≥75 years to ≤84 years 0 1 0 1
≥85 years 1 1 1 1
Total 41 48 41 48
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Subjects who received 2nd Dose of BNT162b2 after unblinding.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:46)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2 unblinded/C4591001 PVP BLA/adsl s9323
Table 13. Exposure to BNT162b2 by Dose, Age Group, and Gender (C4591001 ) –
Open -Label Follow -up Period – Subjects Who Originally Received Placebo
and Then Received BNT162b2 After Unblinding
Number of Subjects
Exposed to BNT162b2 Total Number of Vaccine
Doses
Dose
Age Group Male Female Male Female
Vaccine 30 µg
≥12 years to ≤15 yearsa 26 23 36 32
≥16 years to ≤17 years 152 141 250 229
≥18 years to ≤55 years 5424 5708 9450 10101
>55 years to ≤64 years 1973 2012 3602 3713
≥65 years to ≤74 years 1801 1613 3530 3170
≥75 years to ≤84 years 495 311 976 613
≥85 years 13 4 25 8
Total 9884 9812 17869 17866
Note: 30 μg includes data from phase 1 and phase 2/3.
a. Includes subjects who became eligible for unblinding at 16 years of age, confirmed to have received
placebo originally and then received BNT162b2 post unblinding.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generatio n:
27MAR2021 (12:46)
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220705
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 32
Table 13. Exposure to BNT162b2 by Dose, Age Group, and Gender (C4591001 ) –
Open -Label Follow -up Period – Subjects Who Originally Received Placebo
and Then Received BNT162b2 After Unblinding
Number of Subjects
Exposed to BNT162b2 Total Number of Vaccine
Doses
Dose
Age Group Male Female Male Female
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_PVP_BLA/adsl_s932_open
Table 14. Exposure to BNT162b2 by Dose, Age Group, and Gender (BNT162 -01)
No. of Subjects Exposed to
BNT162b2 Total No. of Vaccine Doses
Dose
Age Group Male Female Male Female
Vaccine 1 µg
≥18 years to ≤64 years 7 5 14 9
≥65 years to ≤74 years 0 0 0 0
≥75 years to ≤84 years 0 0 0 0
Total 7 5 14 9
Vaccine 3 µg
≥18 years to ≤64 years 5 7 10 14
≥65 years to ≤74 years 0 0 0 0
≥75 years to ≤84 years 0 0 0 0
Total 5 7 10 14
Vaccine 10 µg
≥18 years to ≤64 years 8 10 16 19
≥65 years to ≤74 years 3 2 6 4
≥75 years to ≤84 years 1 0 2 0
Total 12 12 24 23
Vaccine 20 µg
≥18 years to ≤64 years 7 10 14 20
≥65 years to ≤74 years 1 5 2 10
≥75 years to ≤84 years 0 1 0 2
Total 8 16 16 32
Vaccine 30 µg
≥18 years to ≤64 years 10 8 20 16
≥65 years to ≤74 years 2 4 4 8
≥75 years to ≤84 years 0 0 0 0
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220706
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 33
Table 14. Exposure to BNT162b2 by Dose, Age Group, and Gender (BNT162 -01)
No. of Subjects Exposed to
BNT162b2 Total No. of Vaccine Doses
Dose
Age Group Male Female Male Female
Total 12 12 24 24
PFIZER CONFIDENTIAL SDTM Creation: 24NOV2020 (15:06) Source Data: adsl Table Generation: 10MAR2021
(11:53) (Cutoff date:23OCT2020 , Snapshot Date: 23OCT2020)
Output File: ex_b2_age_dose_sex rtf
Table 15. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥12 years to ≤15 years
Vaccine 30 µg
Racial origin
White 971 1937
Black or African American 52 103
Asian 72 143
American Indian or Alaska Native 4 8
Native Hawaiian or other Pacific Islander 3 6
Multiracial 23 46
Not reported 6 12
Total 1131 2255
Ethnic origin
Hispanic/Latino 132 263
Non-Hispanic/non -Latino 997 1988
Not reported 2 4
Total 1131 2255
≥16 years to ≤17 years
Vaccine 30 µg
Racial origin
White 309 614
Black or African American 30 60
Asian 22 44
American Indian or Alaska Native 4 8
Native Hawaiian or other Pacific Islander 3 6
Multiracial 10 20
Total 378 752
Ethnic origin
Hispanic/Latino 49 98
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220707
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 34
Table 15. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Non-Hispanic/non -Latino 329 654
Total 378 752
≥18 years to ≤55 years
Vaccine 10 µg
Racial origin
White 11 22
Asian 1 2
Total 12 24
Ethnic origin
Hispanic/Latino 1 2
Non-Hispanic/non -Latino 11 22
Total 12 24
Vaccine 20 µg
Racial origin
White 10 20
Black or African American 2 4
Total 12 24
Ethnic origin
Hispanic/Latino 1 2
Non-Hispanic/non -Latino 11 22
Total 12 24
Vaccine 30 µg
Racial origin
White 9923 19637
Black or African American 1400 2764
Asian 683 1358
American Indian or Alaska Native 161 311
Native Hawaiian or other Pacific Islander 40 80
Multiracial 427 851
Not reported 71 142
Total 12705 25143
Ethnic origin
Hispanic/Latino 4000 7874
Non-Hispanic/non -Latino 8650 17160
Not reported 55 109
Total 12705 25143
>55 years to ≤64 years
Vaccine 30 µg
Racial origin
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220708
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 35
Table 15. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
White 3719 7388
Black or African American 430 849
Asian 135 267
American Indian or Alaska Native 30 58
Native Hawaiian or other Pacific Islander 8 15
Multiracial 76 152
Not reported 10 20
Total 4408 8749
Ethnic origin
Hispanic/Latino 965 1903
Non-Hispanic/non -Latino 3413 6786
Not reported 30 60
Total 4408 8749
≥65 years to ≤74 years
Vaccine 10 µg
Racial origin
White 12 24
Total 12 24
Ethnic origin
Non-Hispanic/non -Latino 12 24
Total 12 24
Vaccine 20 µg
Racial origin
White 9 18
Total 9 18
Ethnic origin
Non-Hispanic/non -Latino 9 18
Total 9 18
Vaccine 30 µg
Racial origin
White 3272 6528
Black or African American 219 437
Asian 82 164
American Indian or Alaska Native 22 44
Native Hawaiian or other Pacific Islander 6 12
Multiracial 30 60
Not reported 10 20
Total 3641 7265
Ethnic origin
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220709
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 36
Table 15. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Hispanic/Latino 583 1158
Non-Hispanic/non -Latino 3038 6067
Not reported 20 40
Total 3641 7265
≥75 years to ≤84 years
Vaccine 20 µg
Racial origin
White 3 6
Total 3 6
Ethnic origin
Non-Hispanic/non -Latino 3 6
Total 3 6
Vaccine 30 µg
Racial origin
White 838 1673
Black or African American 22 44
Asian 31 62
American Indian or Alaska Native 3 6
Native Hawaiian or other Pacific Islander 1 2
Multiracial 7 14
Total 902 1801
Ethnic origin
Hispanic/Latino 107 213
Non-Hispanic/non -Latino 789 1576
Not reported 6 12
Total 902 1801
≥85 years
Vaccine 30 µg
Racial origin
White 20 38
Asian 1 2
American Indian or Alaska Native 1 2
Multiracial 1 2
Total 23 44
Ethnic origin
Hispanic/Latino 2 4
Non-Hispanic/non -Latino 21 40
Total 23 44
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220710
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 37
Table 15. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Blinded Placebo -Controlled Follow -up Period
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Note: 30 μg includes data from phase 1 and phase 2/3.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:46)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2 unblinded/C4591001 PVP BLA/adsl s942
Table 16. Exposure to BNT162b2 by Age G roup, Dose, and Race/Ethnic Origin
(C4591001) – Open -Label Follow -up Period – Subjects Who Originally
Received BNT162b2
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥16 years to ≤17 years
Vaccine 30 µg
Racial origin
White 3 3
Total 3 3
Ethnic origin
Non-Hispanic/non -Latino 3 3
Total 3 3
≥18 years to ≤55 years
Vaccine 30 µg
Racial origin
White 46 46
Black or African American 2 2
Asian 2 2
American Indian or Alaska Native 8 8
Total 58 58
Ethnic origin
Hispanic/Latino 31 31
Non-Hispanic/non -Latino 27 27
Total 58 58
>55 years to ≤64 years
Vaccine 30 µg
Racial origin
White 14 14
Asian 1 1
American Indian or Alaska Native 2 2
Total 17 17
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220711
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 38
Table 16. Exposure to BNT162b2 by Age G roup, Dose, and Race/Ethnic Origin
(C4591001) – Open -Label Follow -up Period – Subjects Who Originally
Received BNT162b2
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Ethnic origin
Hispanic/Latino 10 10
Non-Hispanic/non -Latino 7 7
Total 17 17
≥65 years to ≤74 years
Vaccine 30 µg
Racial origin
White 8 8
Total 8 8
Ethnic origin
Hispanic/Latino 5 5
Non-Hispanic/non -Latino 3 3
Total 8 8
≥75 years to ≤84 years
Vaccine 30 µg
Racial origin
White 1 1
Total 1 1
Ethnic origin
Non-Hispanic/non -Latino 1 1
Total 1 1
≥85 years
Vaccine 30 µg
Racial origin
White 2 2
Total 2 2
Ethnic origin
Non-Hispanic/non -Latino 2 2
Total 2 2
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Subjects who received 2nd Dose of BNT162b2 after unblinding.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:46)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2 unblinded/C4591001 PVP BLA/adsl s9423
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220712
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 39
Table 17. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Open -Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥12 years to ≤15 yearsa
Vaccine 30 µg
Racial origin
White 45 62
Asian 3 5
Multiracial 1 1
Total 49 68
Ethnic origin
Hispanic/Latino 2 4
Non-Hispanic/non -Latino 47 64
Total 49 68
≥16 years to ≤17 years
Vaccine 30 µg
Racial origin
White 251 410
Black or African American 11 19
Asian 14 25
American Indian or Alaska Native 2 4
Native Hawaiian or other Pacific Islander 1 2
Multiracial 12 16
Not reported 2 3
Total 293 479
Ethnic origin
Hispanic/Latino 26 43
Non-Hispanic/non -Latino 266 434
Not reported 1 2
Total 293 479
≥18 years to ≤55 years
Vaccine 30 µg
Racial origin
White 8806 15340
Black or African American 1087 1899
Asian 619 1136
American Indian or Alaska Native 128 236
Native Hawaiian or other Pacific Islander 17 32
Multiracial 405 781
Not reported 70 127
Total 11132 19551
Ethnic origin
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220713
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 40
Table 17. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Open -Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Hispanic/Latino 3441 5300
Non-Hispanic/non -Latino 7635 14157
Not reported 56 94
Total 11132 19551
>55 years to ≤64 years
Vaccine 30 µg
Racial origin
White 3416 6271
Black or African American 331 592
Asian 120 227
American Indian or Alaska Native 35 67
Native Hawaiian or other Pacific Islander 4 7
Multiracial 63 120
Not reported 16 31
Total 3985 7315
Ethnic origin
Hispanic/Latino 901 1560
Non-Hispanic/non -Latino 3067 5724
Not reported 17 31
Total 3985 7315
≥65 years to ≤74 years
Vaccine 30 µg
Racial origin
White 3093 6076
Black or African American 187 360
Asian 78 154
American Indian or Alaska Native 20 39
Native Hawaiian or other Pacific Islander 6 12
Multiracial 22 43
Not reported 8 16
Total 3414 6700
Ethnic origin
Hispanic/Latino 547 1060
Non-Hispanic/non -Latino 2842 5590
Not reported 25 50
Total 3414 6700
≥75 years to ≤84 years
Vaccine 30 µg
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220714
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 41
Table 17. Exposure to BNT162b2 by Age Group, Dose, and Race/Ethnic Origin
(C4591001) – Open -Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding
Age Group
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Racial origin
White 752 1483
Black or African American 22 42
Asian 17 34
American Indian or Alaska Native 4 8
Multiracial 6 12
Not reported 5 10
Total 806 1589
Ethnic origin
Hispanic/Latino 89 174
Non-Hispanic/non -Latino 706 1393
Not reported 11 22
Total 806 1589
≥85 years
Vaccine 30 µg
Racial origin
White 15 29
Asian 1 2
Multiracial 1 2
Total 17 33
Ethnic origin
Non-Hispanic/non -Latino 17 33
Total 17 33
Note: 30 μg includes data from phase 1 and phase 2/3.
a. Includes subjects who became eligible for unblinding at 16 years of age, confirmed to have received
placebo originally and then received BNT162b2 post unblinding.
PFIZER CONFIDENTIAL SDTM Creatio n: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:46)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2 unblinded/C4591001 PVP BLA/adsl s942 open
Table 18. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) –
Blinded Placebo -Controlled Follow -up Period
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 10 µg
Racial origin
White 23 46
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220715
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 42
Table 18. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) –
Blinded Placebo -Controlled Follow -up Period
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Asian 1 2
Total 24 48
Ethnic origin
Hispanic/Latino 1 2
Non-Hispanic/non -Latino 23 46
Total 24 48
Vaccine 20 µg
Racial origin
White 22 44
Black or African American 2 4
Total 24 48
Ethnic origin
Hispanic/Latino 1 2
Non-Hispanic/non -Latino 23 46
Total 24 48
Vaccine 30 µg
Racial origin
White 19052 37815
Black or African American 2153 4257
Asian 1026 2040
American Indian or Alaska Native 225 437
Native Hawaiian or other Pacific Islander 61 121
Multiracial 574 1145
Not reported 97 194
Total 23188 46009
Ethnic origin
Hispanic/Latino 5838 11513
Non-Hispanic/non -Latino 17237 34271
Not reported 113 225
Total 23188 46009
Note: 30 μg includes data from phase 1 and phase 2/3.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:47)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2_unblinded/C4591001_PVP_BLA/adsl_s952
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220716
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 43
Table 19. Exposure to BNT162b2 by Dose and Race/Ethnic Orig in (C4591001) –
Open -Label Follow -up Period – Subjects Who Originally Received
BNT162b2
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 30 µg
Racial origin
White 74 74
Black or African American 2 2
Asian 3 3
American Indian or Alaska Native 10 10
Total 89 89
Ethnic origin
Hispanic/Latino 46 46
Non-Hispanic/non -Latino 43 43
Total 89 89
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Subjects who received 2nd Dose of BNT162b2 after unblinding.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:47)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2 unblinded/C4591001 PVP BLA/adsl s9523
Table 20. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) –
Open -Label Follow -up Period – Subjects Who Originally Received Placebo
and Then Received BNT162b2 After Unblinding
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Vaccine 30 µg
Racial origin
White 16378 29671
Black or African American 1638 2912
Asian 852 1583
American Indian or Alaska Native 189 354
Native Hawaiian or other Pacific Islander 28 53
Multiracial 510 975
Not reported 101 187
Total 19696 35735
Ethnic origin
Hispanic/Latino 5006 8141
Non-Hispanic/non -Latino 14580 27395
Not reported 110 199
Total 19696 35735
090177e198e19252\Final\Final On: 15-Dec-2021 09:55 (GMT)
FDA-CBER-2022-5812-0220717
BNT162b2
1.16 Risk Management Plan (Non -REMS) for Biologic License Application # 125742
CONFIDENTIAL
Page 44
Table 20. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (C4591001) –
Open -Label Follow -up Period – Subjects Who Originally Received Placebo
and Then Received BNT162b2 After Unblinding
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
Note: 30 μg includes data from phase 1 and phase 2/3.
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data: adsl Table Generation:
27MAR2021 (12:47)
(Cutoff Date: 13MAR2021, Snapshot Date: 25MAR2021) Output File:
./nda2 unblinded/C4591001 PVP BLA/adsl s952 open
Table 21. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (BNT162 -01)
Dose
Race/Ethnic Origin No. of Subjects Exposed to
BNT162b2 Total No. of Vaccine Doses
Vaccine 1 µg
Racial Origin
White 12 23
Total 12 23
Ethnic Origin
Non-Hispanic/non -Latino 12 23
Total 12 23
Vaccine 3 µg
Racial Origin
White 12 24
Total 12 24
Ethnic Origin
Non-Hispanic/non -Latino 12 24
Total 12 24
Vaccine 10 µg
Racial Origin
White 24 47
Total 24 47
Ethnic Origin
Non-Hispanic/non -Latino 24 47
Total 24 47
Vaccine 20 µg
Racial Origin
White 24 48
Total 24 48
Ethnic Origin
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Table 21. Exposure to BNT162b2 by Dose and Race/Ethnic Origin (BNT162 -01)
Dose
Race/Ethnic Origin No. of Subjects Exposed to
BNT162b2 Total No. of Vaccine Doses
Non-Hispanic/non -Latino 24 48
Total 24 48
Vaccine 30 µg
Racial Origin
White 24 48
Total 24 48
Ethnic Origin
Non-Hispanic/non -Latino 24 48
Total 24 48
Only race, ethnic origins collected on the case report form with a count of at least one in either column are displayed
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Table 22. Exposure to BNT162b2 (30 μg) by Special Population (C4591001) – Blinded
Placebo -Controlled Follow -up Period
Population Number of Subjects
Exposed
to BNT162b2 (30 μg)
(Na=23188)
nb Total Number
of
Vaccine Doses
Subjects with any baseline comorbidity 10371 26487
AIDS/HIV 100 196
Any Malignancy + Metastatic Solid Tumor + Leukemia +
Lymphoma 852 1696
Chronic Pulmonary Disease 1901 3774
Renal Disease 140 279
Rheumatic Disease 75 147
Mild Liver Disease + Moderate or Severe Liver Disease 154 302
Cerebrovascular Disease + Peripheral Vascular Disease +
Myocardial Infarction + Congestive Heart Failure 651 1298
Dementia 7 14
Diabetes With/Without Chronic Complication 1706 3385
Hemiplegia or Paraplegia 4 8
Peptic Ulcer Disease 63 126
Obese 7689 15262
Note: Comorbidity is based on Charlson Comorbidity Index categories. Participants identified as belonging to
these categories were identified by medical history data collected during the study.
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Hemiplegia or Paraplegia only includes p referred terms Hemiplegia and Paraplegia.
a. N = number of subjects in the specified group.
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Table 22. Exposure to BNT162b2 (30 μg) by Special Population (C4591001) – Blinded
Placebo -Controlled Follow -up Period
Population Number of Subjects
Exposed
to BNT162b2 (30 μg)
(Na=23188)
nb Total Number
of
Vaccine Doses
b. n = Number of subjects reporting at least 1 occurrence of any comorbidity or obese (BMI ≥30 kg/m2 [≥16
Years of age] or BMI ≥95th percentile [12 -15 Years of age]).
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Table 23. Exposure to BNT162b2 (30 μg) by Special Population (C4591001) – Open -
Label Follow -up Period – Subjects Who Originally Received Placebo and
Then Received BNT162b2 After Unblinding
Population Number of Subjects
Exposed
to BNT162b2 (30 μg)
(Na=19696)
nb Total Number
of
Vaccine Doses
Subjects with any baseline comorbidity 8981 21590
AIDS/HIV 86 161
Any Malignancy + Metastatic Solid Tumor + Leukemia +
Lymphoma 734 1406
Chronic Pulmonary Disease 1590 2953
Renal Disease 139 262
Rheumatic Disease 66 122
Mild Liver Disease + Moderate or Severe Liver Disease 102 193
Cerebrovascular Disease + Peripheral Vascular Disease +
Myocardial Infarction + Congestive Heart Failure 567 1075
Dementia 9 17
Diabetes With/Without Chronic Complication 1555 2928
Hemiplegia or Paraplegia 4 8
Peptic Ulcer Disease 76 145
Obese 6760 12320
Note: Comorbidity is based on Charlson Comorbidity Index categories. Participants identified as belonging to
these categories were identified by medical history data collected during the study.
Note: 30 μg includes data from phase 1 and phase 2/3.
Note: Hemiplegia or Paraplegia only includes p referred terms Hemiplegia and Paraplegia.
a. N = number of subjects in the specified group.
b. n = Number of subjects reporting at least 1 occurrence of any comorbidity or obese (BMI ≥30 kg/m2 [≥16
Years of age] or BMI ≥95th percentile [12 -15 Years of age]).
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Table 28. Exposure to BNT162b2 by Race/Ethnic Origin (C4591001) – 12-15 Years
– Blinded Placebo -Controlled Follow -up Period
Age Groupa
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥12 years to ≤15 years
Vaccine 30 µg
Racial origin
White 970 1935
Black or African American 52 103
Asian 72 143
American Indian or Alaska
Native 4 8
Native Hawaiian or other Pacific
Islander 3 6
Multiracial 24 48
Not reported 6 12
Total 1131 2255
Ethnic origin
Hispanic/Latino 132 263
Non-Hispanic/non -Latino 997 1988
Not reported 2 4
Total 1131 2255
a. Based on age at vaccination.
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Table 29. Exposure to BNT162b2 by Race/Ethnic Origin (C4591001) – 12-15 Years
– Open -Label Follow -up Period – Subjects Who Originally Received
Placebo and Then Received BNT162b2 After Unblinding
Age Groupa
Dose
Race/Ethnic Origin Number of Subjects
Exposed to BNT162b2 Total Number of
Vaccine Doses
≥12 years to ≤15 years
Vaccine 30 µg
Racial origin
White 866 1718
Black or African American 48 96
Asian 62 123
American Indian or Alaska
Native 2 3
Multiracial 26 52
Not reported 6 10
Total 1010 2002
Ethnic origin
Hispanic/Latino 115 222
Non-Hispanic/non -Latino 892 1774
Not reported 3 6
Total 1010 2002
a. Based on age at vaccination. Includes subjects who became eligible for unblinding at 16 years of age,
confirmed to have received placebo originally and then received BNT162b2 post unblinding.
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Table 31. Exposure to BNT162b2 (30 μg) by Special Population (C4591001) – 12-15
Years – Open -Label Follow -up Period – Subjects Who Originally
Received Placebo and Then Received BNT162b2 After Unblinding
Population Number of Subjects Expo sed
to BNT162b2 (30 μg)
(Na=1010)
nb Total Number of
Vaccine Doses
Subjects with any baseline
comorbidity 214 425
Chronic Pulmonary Disease 114 226
Rheumatic Disease 2 4
Diabetes With/Without Chronic
Complication 2 4
Obese 116 229
Note: Includes subjects who became eligible for unblinding at 16 years of age.
Note: Includes subjects confirmed to have received placebo originally and then received BNT162b2 post
unblinding.
Note: Comorbidity is based on Charlson Comorbidity Index categories. Participants identified as belonging
to these categories were identified by medical history data collected during the study.
Note: Hemiplegia or Paraplegia only includes preferred terms Hemiplegia and Paraplegia. No participants
were identified.
a. N = number of subjects in the specified group.
b. n = Number of subjects reporting at least 1 occurrence of any comorbidity or obese ( BMI
≥95th percentile [12 -15 Years of age]).
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2.1.2.a.2. Inclusion and Exclusion Criteria
Detailed descriptions of all inclusion and exclusion criteria for clinical studies are provided
in the individual CSRs which were filed to IND 019736 .
Inclusion criteria
• Healthy participants who are determined by medical history, physical examination
(if required), and clinical judgm ent of the investigator to be eligible for inclusion in the
study.
• Healthy participants with pre -existing stable disease, defined as disease not requiring
significant change in therapy or hospitalization for worsening disease during the 6 weeks
before enr ollment, can be included. In order for the overall Phase 3 study population to
be as representative and diverse as possible, the inclusion of participants with known
chronic stable infection with HIV, HCV, or HBV was permitted as the study progressed .
Specific criteria for these Phase 3 participants can be found in the C4591001 protocol,
Section 10. 8.
• Phase 2/3 only : Participants who, in the judgment of the investigator, are at higher risk
for acquiring COVID -19 (including, bu t not limited to, use of mass transportation,
relevant demographics, front -line essential workers , and others).
• The participants enrolled were 12 years of age and older; the 12 - to 15 -year-old cohort
was included in the protocol in October 2020.
Exclusio n criteria
Phase 1 exclusion criteria were stricter than criteria in Phases 2 and 3 of the study.
Participants were excluded from the studies according to the general criteria listed below :
• Previous vaccination with any coronavirus vaccine
Reason for exclusion : To avoid confounding the assessment of serological or clinic al
immune response in the study population.
Is it considered to be included as missing information ? No .
Rationale : Minimal potential clinical impact on the target population .
• Previous c linical or microbiological diagnosis of COVID -19
Reason for exclusion : Phase 1 excluded participants with a previous clinical or
microbiological diagnosis of COVID -19 because these participants may have some
degree of protection from subsequent infection by SARS -CoV -2 and therefore would
confound the pivotal efficacy endpoint. During Phase 2/3, participants with prior
undiagnosed infecti on were allowed to be enrolled. Screening for SAR S-CoV -2 with
nucleic acid amplificat ion test by nasal swab or antibodies to non -vaccine SARS -CoV -2
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antigen by serology was not conducted before vaccine administration in Phase 2/3, but
samples were taken to run these assays after vaccination, thus identifying participants
with unidentified prior in fection. This group will be assessed to identify whether prior
infection affect s safety .
Is it considered to be included as missing information? No.
Rationale : Safety in study participants with prior infection will be assessed in the pivotal
study .
• Immunocompromised individuals with known or suspected immunodeficiency, as
determined by history and/or laboratory/physical examination .
Reason for exclusion : Immunocompromised participants may have impaired immune
responses to vaccines and would therefore limit the ability to demonstrate efficacy,
which is the primary pivotal endpoint.
Is it considered to be included as missing information ? No.
Rationale : Participants with potential immunodeficient status were not specifically
included in the study population. However, since the study population is intended to be
as representative as possible of the vulnerable population to COVID -19 illness ,
sub-analyses of immunogenicity data in future studies may provide further understanding
of immune responses in this population .
• Receipt of blood/plasma products or immunoglobulin, from 60 days before study
intervention administration or planned receipt throughout the study
Reason for exclusion : To avoid confounding the assessment of serologi cal or clinical
immune response in the study population.
Is it considered to be included as missing information ? No.
Rationale : No impact on the safety of the target population.
• Women who are pregnant or breastfeeding
Reason for exclusion : To avoid use in a vulnerable population .
Is it considered to be included as missing information? Yes.
Rationale : It is not known if maternal Maternal vaccination with BNT162b2 would
have COVID -19 mRNA vaccine is being studies in C4591015 to explore unexpected
negative co nsequences to the embryo or fetus foetus .
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• Other medical or psychiatric condition including recent (within the past year) or
active suicidal ideation/behavior or laboratory abnormality that may increase the
risk of study participation or, in the investigator’s judgment, make the participant
inappropriate for the study
Reason for exclusion : To avoid misleading results deriving from non -compliance to
study procedures .
Is it considered to be included as missing information ? No .
Rationale : Safety prof ile of BNT162b2 is not expected to differ in these subjects when
properly administered.
2.1.2.a.2.1. Non-Study Post -Authori zation Exposure
Cumulatively, through 18 June 30 September 2021, approximately 774,478,4401,709,812,866
doses of BNT162 b2 were shipped worldwide, corresponding to 642,817,105 approximately
1,402,241,841 estimated administered doses.
The worldwide number of shipped doses may serve as a reasonable indicator of subject
exposure, considering that approximately 8382% of the shippe d doses were administered.
Cumulative worldwide estimated exposure3 by dose, and region based on or extrapolated
from internal data (number of shipped doses) and published data (number of doses
administered) is displayed in Table 27.
The estimated cumulative number of shipped and administered doses of BNT162b2 by
region based on data provided in the shipment tracker (Order Book),4 from the receipt of the
first temporary authori zation for emergency supply on 01 December 2020 through 3 0
September 2021, are summarized in Table 32.
Table 32. Cumulative Estimated Shipped and /Administered Doses of BNT162b2 by
Region Worldwide , through 18 June 2021
Region/Country/Ot
her % of Doses Total Number of Shipped
Doses Total Number of
Administered Doses
Europe 41.81% 323502270 7032671
10 268506884 5714739
11
European Unionaa
(27) 33.330.0
% 257628345 5135057
85 213831526 4159396
86
Additional EEA
Countriesaa (3) 0.54% 3559335 7006155 2954248 5674986
Switzerlanda 0.3% 4500990 3690812
3 Including data from license partners.
4 The Order Book is the most accurate tracker of shipment used as data source for all the Regions and
Countries; US shipment data not available in the Order Book were taken from the Order Management
Dashboard and data for Fosun License Partner territories, Hong Kong and Macau, were provided by BioNTech.
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Table 32. Cumulative Estimated Shipped and /Administered Doses of BNT162b2 by
Region Worldwide , through 18 June 2021
Region/Country/Ot
her % of Doses Total Number of Shipped
Doses Total Number of
Administered Doses
UKb 3.6% 61213230 50194849
Other Countriesbc 8.06.3% 62314590 10721704
5 51721110 87917977
Commonwealth of
Independent Statesd 0.6% 9823905 8055602
North Americace 29.818.5
% 230593605 3160936
95 191392692 2645972
40
US 26.615.8
% 205645305 2700205
05 170685603 2268172
24
Canada 3.2.7% 24948300 46073190 20707089 37780016
Central and South
Americadf 7.412.5
% 57644730 21308568
0 47845126 17473025
8
Asia 19.523.6
% 150739485 4040775
81 125113773 3313436
16
JapanaJapana 12.210.7
% 94169790 18349812
0 78160926 15046845
8
Other
CountrieseOther
Countriesg 7.312.9
% 56569695 22057946
1 46952847 18087515
8
Oceania 0.71.4% 5681520 23158980 4715662 18990364
Australia/New
Zealand Zealanda 0.71.4% 5681520 23158980 4715662 18990364
Other Countries 0.0% 0 0
AfricafAfricah 0.82.9% 6316830 50129820 5242969 41106452
Total 100.0 % 774478440 1709812
866 642817105 1402241
841
a. Conditional approval. In this Region BNT162b2 was conditionally approved;
b. Includes:
In the UK, with both authorisation the aut horization for emergency supply under regulation 174 and the
conditional marketing authorisation authori zation approval , are currently active for BNT162b2 .
c. Includes Albania, Kosovo , and North Macedonia and Switzerland with conditional approval,
Georgia where BNT162b2 was conditionally approved , Serbia and Ukraine with where it received
authoriz ation for emergency supply,
Azerbaijan, Bosnia and Moldova where BNT162b2 it was shipped for COVAX, Turkey where it was shipped
according to a pharmacovigilance agreement in place by the MAH and the Turkish government ;
c. Authorization for emergency supply.
d. Includes : Georgia and Ukraine where BNT162b2 received authorization for emergency supply and
Moldova where it was conditionally approved; in Azerbaijan BNT162b2 was shipped for COVAX, and
Tajikistan and Uzbekistan are part of US government donations;
Brazil and Peru with conditional approval,
e. In this Region BNT162b2 initially received authorization for emergency supply; in the US, a full
approval ( BLA ) was also granted on 23 August 2021 and in Canada a full approval (NDS) replacing th e
pre-existing authorization for emergency supply was granted during the current reporting period on
16 September 2021 ;
f. Includes Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, El Salvador, Honduras, Mexico,
Panama , Paraguay and Uruguay with authorisation where BNT162b2 received authori zation for emergency
supply, Argentina, Brazil and Peru where BNT162b2 was conditionally approved; Bolivia where BNT162b2
was shipped for COVAX and Guatemala where BNT162b2 was shipped for COVAX and Antigua&Barbuda,
Bahamas, Barbados, Belize, Dominica, Grenada, Guyana, Jamaica, St Kitts&Nevis, St. Lucia,
StVin&Grenadine, Suriname and Trinidad&Tobago that are part of US Government donations ;
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Table 32. Cumulative Estimated Shipped and /Administered Doses of BNT162b2 by
Region Worldwide , through 18 June 2021
Region/Country/Ot
her % of Doses Total Number of Shipped
Doses Total Number of
Administered Doses
g. Includes :
Hong Kong, Malaysia and South Korea with conditional approval,
Bahrain, Bhutan, Indonesia, Iraq, Israel, Jordan, Kuwait, Lebanon, Macau, Maldives, Mongolia, Oman,
Pakistan, Palestine, Pakistan Philippines , Qatar, Saudi Arabia, Singapore, Sri Lanka and, United Arab Emirates
withand Vietnam where BNT162b2 received authorization for emergency supply ,
; Hong Kong, Malaysia, South Korea and Thailand where BNT162b2 was conditionally approved and
Bangladesh, Bhutan, Laos , Maldives, Mongolia, Philippines and West Bank & Gaza where BNT162b2 was
shipped for COVAX;
h. Includes f. Includes:
Rwanda, Tunisia and South Africa where BNT162b2 received authorisation for emergency supply,
Angola, Botswana, Cape Verde, Chad, Ivory Coast, Libya Lybia and Togo where BNT162b2 was shipped for
COVAX ; Benin, Congo, Gabon, Namibia, Seychelles, Sierra Leone and Uganda that are parts of US
Government donations ; Botswana, Egypt, Eswatini, Kenya, Mauritius, Morocco, Rwan da, South Africa and
Tunisia where BNT162b2 received authori zation for emergency supply .
Out of the total shipped and administered doses, 213,475,665 and 177,184,802 respectively,
were shipped to Rest Of World (Non EEA countries, Canada, Central and Sout h America,
Asian countries [excluding Japan], Oceania and Africa).
Method Used to Calculate Exposure
Not applicable.
Exposure
Not applicable.
2.1.2.a.3. Regulatory Actions Related to Safety
There were no withdrawals for safety reasons up to 28 February 30 September 2021.
2.1.2.b. Populations Not Studied in the Pre -Approval Phase
There has been limited exposure to BNT162b2 in some special populations and no
epidemiologic studies have been conducted in p regnant/lactating women, pediatric
participants (<12 years of age), and specific subpopulation s that were initially excluded from
the BNT162b2 program.
Table 33. Exposure of Special Populations Included or not in Clinical Trial
Development Programs
Type of special population Exposure
Pregnant women Available data on BNT162b2 administered to pregnant women are
insufficient to inform on vaccine -associated risks in pregnancy. In a
reproductive and developmental toxicity study , no vaccine -related
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Table 33. Exposure of Special Populations Included or not in Clinical Trial
Development Programs
Type of special population Exposure
adverse effects on female fertility, fetal development , or postnatal
development were reported.
Participants 16 years of age and older
Through the cut-off date of 13 March 2021, there were 50 cases ( 52
events) originating from Study C4591001 in participant 16 years of
age and older , and all were unique pregnancies.
Participants in Booster group 12-15 years of age
Through the cut -off date of 17 June 02 September 2021, there w ere no
CT cases originating of pregnancies from Study study C4591001 in
participants enrolled in the booster group .12-15 years of age .
Breastfeeding women Breastfeeding women were not initially included in the BNT162b2
clinical development program .
Data are not available to assess the effects of BNT162b2 on the
breastfed infant or on milk production/excretion.
The developmental and health benefits of breastfeeding should be
considered along with the mother’s clinical need for BNT162b2 and
any potential adverse effects on the breastfed child from BNT162b2
or from the underlying maternal condition. For preventive vaccines,
the underlying maternal condition is susceptible to disease prevented
by the vaccine.
Participants 16 years of age and older
Through the cut-off date of 13 March 2021, there were no CT cases
indicative of exposure during breastfeeding from study C4591001 in
participants 16 years of age and older .
Participants in Booster group 12-15 years of age
Through the cut -off date of 17 June 02 September 2021, there were no
CT cases indicative of exposure during breastfeeding originating from
Study study C4591001 in participants enrolled in the booster
group 12-15 years of age .
Participants with relevant
comorbidities:
• Participants with hepatic
impairment
• Participants with renal i mpairment
• Participants with cardiovascular
disease
• Immunocompromised participants
• Participants with a disease
severity different from inclusion
criteria in CTs Healthy participants with pre -existing stable disease, defined as
disease not requiring significant change in therapy or hospitalization
for worsening disease during the 6 weeks before enrollment, were
included . This allow ed enrol lment of a proportion of participants
with common comorbidities such as cardiovascular diseases including
hypertension, chronic pulmonary diseases , asthma, chronic liver
disease, BMI >30 kg/m2, participants with stage 3 or worse chronic
kidney disease , and participants with varying disease severity .
Participants with potenti al immunodeficient status were not
specifically included in the study population .
Please refer to Table 22, Table 23, Table 30 and Table 26Table 31 for
the exposure of special populations.
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Table 33. Exposure of Special Populations Included or not in Clinical Trial
Development Programs
Type of special population Exposure
Participants of different racial
and/or ethnic origin Please refer to Table 21Table 15, Table 16, Table 17, Table 18,
Table 19, Table 20, Table 21, Table 28 and Table 25Table 29 for
exposure information by ethnic origin from the studies.
Subpopulations carrying known and
relevant polymorphisms No data available .
Pediatric participants The safety and effectiveness of BNT162b2 in individuals younger
than 16 5 years of age have not been established.
Participants 16 to 17 years of age and older
A total of 671 p ediatric participants 16 to 17 years of age received
BNT162b2 through the DLP of 13 March 2021 :
• 378 participants in the blinded -placebo controlled follow -up
period ( Error! Not a valid result for table. ).
• 293 partic ipants in the open -label follow -up period after the
unblinding ( Table 5).
Participants 12 to 15 years of age
One thousa nd andone hundred eighty (1180 thirty -one (1131) pediatric
participants 12 to 15 years of age received in the blinded controlled
follow -up period; 1010 participants , who originally received placebo,
then received BNT162b2 in the Open -Label Follow -up period after
unblinding through the cut-off date of 13 March 02 September 2021
(Table 3Table 24 and Table 5Table 25).
Elderly (≥ 65 years old) The safety and effectiveness of BNT162b2 in elderly participants was
consistent with that seen in younger adult participants.
Clinical studies of BNT162b2 include d a total of 8846 participants 65
years of age and over ; of these, 8827 were from study C4591001 ,
through the cut -off date of 13 March 2021:
• 4590 participants in the blinded -placebo controlled follow -
up period (Error! Not a valid result for table. )
• 4237 participants in the open -label follow -up period after
unblinding (Table 5).
Nine teen (19) participants 65 years of age and over were from study
BNT 162-01 study through the cut -off date of 23 October 2020
(Table 6).
Abbreviations: EUA = emergency use authorization; BMI = body mass index ; COVID -19 = coronavirus
disease 2019; CT = clinical trial
2.1.2.c. Adverse Events / Adverse Reactions
2.1.2.c.1. Identification of Safety Concern in the Initial PVP Submission
2.1.2.c.1.1. Risks not Considered Important for Inclusion in the List of Safety Concerns
in the PVP
Not all potential or identified risks for the vaccine are considered to meet the level of
importance necessitating inclusion in the list of safety concerns in the PVP:
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• Risks with minimal and temporary clinical impact on patients (in relation to the severity
of the disease prevented) .
• The following reactogenicity events are identified risks not included in the list of safety
concerns in the PVP: Injection site pain, Fever , Chills, Fatigue, Headache, Muscle pain,
and Joint pain.
• Very rare potential risks for any medicinal treatment, including vaccines , which are well
known to healthcare professionals are not included in the list of safety concerns.
2.1.2.c.2. Important Identified a nd Potential Risks and Missing Information
2.1.2.c.2.1. Presentation of Important Identified Risks and Important Potential Risks
Important Identified Risk s
Table 34. Myocarditis and Pericarditis
Potential
mechanisms,
evidence source and
strength of evidence A mechanism of action (MOA) by which the vaccine could cause myocarditis and
pericarditis has not been established. Nonclinical studies, protein sequence
analyses and animal studies in rats and non -human primates have not identified a
MOA. Hypotheses for MOA include an immune stimulated response (including
the possibility of molecular mimicry), a general systemic inflammatory response
from vaccination or a hypersensitivity response.
Characterisation of
the risk
Participants 16 years of age and older
Data from the CT dataseta (cut-off date: 18 June 2021)
Two cases were retrieved with the myocarditis and pericarditis search strategyb in
the clinical trial dataset through the cu t-off date of 18 June 2021. These cases
originated from Phase 3 clinical study C4591001 and are summarized below:
Myocarditis:
There were no cases reporting myocarditis as SAE .
Pericarditis (2 cases ):
Two (2) serious adverse events [PT Pericarditis] wer e reported, both deemed not
related to study treatment by the Investigator.
Data from the safety database : (cut-off date: 18 June 2021) :
Since the first temporary authorization for emergency supply under Regulation 174
in the UK (01 December 2020) and thr ough 18 June 2021, 823 potentially relevant
cases (0.3% of the total post -authorization dataset) were retrieved from the
Myocarditis and Pericarditis search strategy:b 490 cases reported events related to
myocarditis and 371 cases reported events related to pericarditis (in 38 of these
823 cases, the subjects developed both myocarditis and pericarditis related events).
Myocard itis (490 cases ):
These 490 cases were individually reviewed and assessed according to Brighton
Collaboration (BC) Myocarditis Case Definition and Level of Certainty
Classification (version 1.4.2, 30 May 2021), as shown in the Table below:
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Table 34. Myocarditis and Pericarditis
Brighton Collaboration Level Number of cases
BC 1 41
BC 2 44
BC 3 42
BC 4 337
BC 5 26
Total 490
Level 1 indicates a definitive case with the highest level of diagnostic certainty
of myocarditis, level 2 indicates a probable case, and level 3 indicates a possible
case. Level 4 is defined as “reported event of myocarditis with insufficient
evidence to meet the case definition” and Level 5 as not a case of myocarditis.
There were 464 cases meeting BC Level 1 to 4, which are presented below:
Country of incidence: Israel (135), US (78), Germany (76), UK (55), France (21),
Italy, Japan (13 each), Austria (10), Greece, Spain (8 each), Sweden (7), Canada,
Norway (6 each), Ireland (5); the remaining 23 cases originated from 17 different
countries.
Gender: Females (133), Males (325), Unknown (6).
Age (n=443) ranged from 16 to 97 years (mean = 37.2 years, median = 32.0 years).
Reported relevant PTs: Myocarditis (463) and Autoimmune myocarditis (1).
Overall event seriousness and outcome of these 464 cases are summarized below.
Total Events
N = 464 (%)
Serious events 459 (98.9)
Events with Criterion of Hospitalization 337 (72.6)
Distribution of events by Outcome
Outcome: Death 14 (3.0)
Outcome: Resolved/Resolving 149 (32.1)
Outcome: Not resolved 106 (22.8)
Outcome: Resolved with sequelae 10 (2.2)
Outcome: Unknown/No data 185 (39.9)
Pericarditis (371 cases )
Country of incidence: US (68), France (62), Israel (50), UK (38), Italy (33),
Norway, Spain (24 each), Canada (10), Australia (9), Greece (7), Germany (6),
Belgium, Denmark, Netherlands, Switzerland (5 each); the remaining 20 cases
originated from 11 different countries.
Gender: Females (185), Males (181), Unknown (5).
Age (n=335) ranged from 16 to 92 years (mean = 51. 5 years, median = 51.0 years).
Reported relevant PTs: Pericarditis (360) and Pleuropericarditis (12).
Overall event seriousness and outcome of these 371 cases are summarized below.
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Table 34. Myocarditis and Pericarditis
Total Events
N = 372 (%)
Serious events 370 (99.5)
Events with Criterion of Hospitalization 206 (55.4)
Distribution of events by Outcome
Outcome: Death 3 (0.8)
Outcome: Resolved/Resolving 213 (57.3)
Outcome: Not resolved 63 (16 9)
Outcome: Resolved with sequelae 7 (1.9)
Outcome: Unknown/No data 86 (23 1)
Participants 12 to 15 years of age
Data from the CT dataset:adatabase (cut-off date 0 2 September 2021) :
No cases were One (1) case w as retrieved reporting with the Myocarditis and
Pericarditis as SAE search strategyb in the clinical trial dataset CT database through
the cut -off date of 18 June 02 September 2021. This case originated from the
clinical study C4591001.
Myocarditis (1 case) :
One (1) SAE (PT Myocarditis) was reported 3 days after the administration of the
second dose of BNT162b2 ; the participant recovered the following day. The SAE
was deemed not related to study treatment by the investigator.
Pericarditis :
There were no cases reporting pericarditis as SAE.
Data from the safety database : (cut-off date 30 September 2021) :
Through 18 June 30 September 2021, 15180 potentially relevant cases (0.03% of
the total post -authori zation dataset) were retrieved from the Myocarditis and
Pericarditis search strategy:b 13154 cases reported myocarditis and 4 61 cases
report ed pericarditis (in 235 of these 15180 cases, the subjects developed both
myocarditis and pericarditis).
Myocarditis ( 13154 cases )
These 13154 cases were individually reviewed and assessed according to Brighton
Collaboration (BC) Myocarditis Case Definition and Level of Certainty
Classification, as shown in the Table below:
Brighton Collaboration Level Number of cases
BC 1 014
BC 2 09
BC 3 0
BC 4 11130
BC 5 21
Total 13154
Level 1 indicates a definitive case with the highest level of diagnostic certainty
of myocarditis, level 2 indicates a probable case, and level 3 indicates a possible
case. Level 4 is defined as “reported event of myoc arditis with insufficient
evidence to meet the case definition” and Level 5 as not a case of myocarditis.
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Table 34. Myocarditis and Pericarditis
NoThe details of 15 3 cases met BC levels (excluding 1 to 3. There were 11 cases
meeting BC Level 4, which 5 case) are presented below :
Country of incidence: US (10) and Bahrain (1).
Country of incidence: Hong Kong (39), U S (25), Germany (18), France (17), Italy
(8), Israel (7), Austria and Spain (6 each) , Denmark and Japan (5 cases) ; the
remaining 17 cases originated from 13 different countries .
Gender: Female s (20Female (1), Males ( 10130), and not reported (3 ).
Age (n= 11153) ranged from 12 to 15 years (mean = 13.8 9 years,
median = 14.0 years).
Reported relevant PT: Myocarditis ( 11153).
Overall event seriousness and outcome of these 11153 cases are summarized
below.
Total Events
N = 11153 (%)
Serious events 10153* (100 .0)
Events with Criterion of Hospitalization 110 (719)
Distribution of events by Outcome
Outcome: Death 0
Outcome: Resolved/Resolving 3
Outcome: Not resolved 4
Outcome: Resolved with sequelae 0
Outcome: Unknown/No data 4
Pericarditis (4 cases )
Country of incidence: US (4).
Gender: Males (4).
Age (n=4) ranged from 12 to 15 years (mean = 13.5 years, median = 13.5 years).
Reported relevant PT: Pericarditis (4
).
Overall event seriousness and outcome of these 4 cases are summarized below.
Total Events
N = 4
Serious events 3
Events with Criterion of Hospitalization 1
Distribution of events by Outcome
Outcome: Death 0
Outcome: Resolved/Resolving 179 (51. 6)
Outcome: Not resolved 17 (11. 1)
Outcome: Resolved with sequelae 0
Outcome: Unknown/No data 257 (37.3)
*Includes 1 case where myocarditis was captured as non -serious and upgraded
to serious after the DLP.
Pericarditis ( 61 cases )
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Table 34. Myocarditis and Pericarditis
These 61 cases were individually reviewed and assessed according to Brighton
Colloboration (BC) Pericarditis Case Definition and Level of Certainty
Classification , as shown in the Table below
Brighton Collaboration Level Number of cases
BC 1 1
BC 2 4
BC 3 0
BC 4 56
BC 5 0
Total 61
Level 1 indicates a definitive case with the highest level of diagnostic certainty
of pericarditis, level 2 indicates a probable case, and level 3 indicates a
possible case. Level 4 is defined as “reported event of pericarditis with
insufficient evidence to meet the case definition” and Level 5 as not a case of
pericarditis.
The details of 61 cases are presented below:
Country of incidence: Hong Kong (29), Italy (7), France (6), US (4), Canada (3),
Australia, Belgium, Germany, and Japan (2 each); the remaining 4 cases originated
from 4 different countries .
Gender: Males ( 48) and Females (13) .
Age (n= 61) ranged from 12 to 15 years (mean = 14.0 years, median = 14.0 years).
Reported relevant PT: Pericarditis ( 61).
Overall event seriousness and outcome of these Booster Group
Data from the CT database:
Through DLP 17 June 2021, no cases were retrieved reporting myocarditis and
pericarditis in the participants who received booster dose.
Data from the safety database:
Through DLP 18 June 2021, no cases were retrieved reporting myocarditis and
pericarditis in the subjects who received the booster dose .61 cases are summarized
below.
Total Events
N = 61 (%)
Serious events 61 (100 .0)
Events with Criterion of Hospitalization 17 (27 9)
Distribution of events by Outcome
Outcome: Death 0
Outcome: Resolved/Resolving 18 (29 5)
Outcome: Not resolved 9 (14.8)
Outcome: Resolved with sequelae 1 (1.6)
Outcome: Unknown/No data 33 (54 1)
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Table 34. Myocarditis and Pericarditis
Risk factors and risk
groups Post-authorization reports have been received for more males than females, over a
wide age range and following dose 1 and dose 2 of the vaccine. Evaluation by the
US CDC has found reports to be most frequent in adolescent and young adult male
patients following the second dose of vaccine.
Preventability Due to an unknown MOA, preventative measures are not clear for individuals with
or without a personal history of myocarditis or pericarditis.
Impact on the risk -
benefit balance of the
biologic product The vaccine continues to have a favorable risk benefit balance
Public health impact Considering the low rates of myocarditis and pericarditis reported following
vaccination, balanced with the risk of death and illness (including myocarditis)
caused by SARS -CoV -2, the public health impact of post -vaccination myocarditis
and pericarditis is minimal.
a. Please note that CT dataset from the safety database includes only cases rep orting SAEs.
b. Search criteria: the following PTs were used to retrieve cases of Myocarditis and Pericarditis:
Autoimmune myocarditis; Eosinophilic myocarditis; Giant cell myocarditis; Hypersensitivity myocarditis;
Immune -mediated myocarditis; Myocarditis; Autoimmune pericarditis, Pericarditis; Pericardi tis adhesive;
Pericarditis constrictive; Pleuropericarditis.
Table 35. Anaphylaxis
Potential
mechanisms,
evidence source and
strength of evidence Interaction of an allergen with IgE on basophils and mast cells triggers release of
histamine, leukotrienes and other mediators that cause diffuse smooth muscle
contraction and vasodilation with plasma leakage. This can manifest clinically with
dyspnea, hypotension, swelling (sometimes lead ing to airway compromise), and
rash (including hives).
Characterisation of
the risk
Participants 16 years of age and older
Data from the CT data seta (cut-off date 18 June 2021)
Through 18 June 2021,b there was 1 case from the CT dataset (from Phase 3
clinical study C4591001) of serious Anaphylactoid reaction in a 17 -year-old
participant reported as resolved and deemed related t o study treatment by the
Investigator :
Data from the safety database : (cut-off date 18 June 2021) :
Through 18 June 2021,b there were 3822 cases (1.2% of the total post authorization
dataset) reporting a total of 3914 events in individuals 16 years and older including:
Anaphylactic reaction (3414)
Anaphylactic shock (420)
Anaphylactoid rection (75)
Anaphylactoid shock (5)
Overall event seriousness and outcome are summarized below:
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Table 35. Anaphylaxis
Total Events
N = 3914 (%)
Serious events 3868 (98.8)
Events with Criterion of Hospitalization 1231 (31.5)
Distribution of events by Outcome *
Outcome: Death 28 (0.7)
Outcome: Resolved/Resolving 2958 (75.6)
Outcome: Not resolved 171 (4.4)
Outcome: Resolved with sequelae 56 (1.4)
Outcome: Unknown 704 (18)
*For the outcome count, the multiple Lowest Level Terms that code to the same PT
within a case are counted and presented individually Therefore, for selected PTs the
total count of the event outcome may exceed the total number of events
Participants 12 to 15 years of age
Data from the CT dataset : adatabase (cut-off date 02 September 2021)
Through 18 June 02 September 2021 , there were no casesb there were no cases
reporting Anaphylactic reaction/shock, Anaphylactoid reaction/shock as SAEs
from the CT dataset database .
Data from the safety database : (cut-off date 30 September 2021) :
Through 18 June 2021,b30 September 2021, there were 543 cases (4 anaphylacticb
(41 Anaphylactic reaction , 4 Anaphylactic shock , and 1 anaphylactic
shock Anaphylactoid reaction ) in individuals 12 to 15 years of age ; (0.01% of total
post-authori zation dataset) ; overall event seriousness and outcome are summarized
below:
Total Events
N = 546 (%)
Serious events 546 (100)
Events with Criterion of Hospitalization 115 (32.6)
Distribution of events by Outcome
Outcome: Death 0
Outcome: Resolved/Resolving 332 (69.6)
Outcome: Resolved with sequelae 0
Outcome: Not resolved 2 (4 3)
Outcome: Unknown 12 (26.1)
Booster Group :
Data from the CT database:
Through DLP 17 June 2021, b no cases were retrieved reporting anaphylaxis in the
participants who received booster dose.
Data from the safety database:
Through DLP 18 June 2021,b no cases were retrieved reporting anaphylaxis in the
subjects who received the booster dose.
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Table 35. Anaphylaxis
Conclusion: Evaluation of Anaphylactic reaction/shock, Anaphylactoid
reaction/shock cases through 18 Jun 30 September 2021 did not reveal any
significant new safety information. Anaphylaxis is appropriately described in the
product labeling as are non -anaph ylactic hypersensitivity events. Surveillance will
continue.
Risk factors and risk
groups Known hypersensitivity to any components of the vaccine.
Preventability Prevention of anaphylaxis may not be possible, particularly with the 1st dose of a
vaccine; therefore, healthcare professionals administering the vaccine must be
vigilant for early signs and symptoms.
Impact on the risk -
benefit balance of the
biologic product Anaphylactic reaction in an individual can be impactful (medically important)
because it is a potentially life -threatening event requiring medical intervention.
Public health impact Minimal due to rarity of the event. Although the potential clinical consequences of
an anaphylactic reaction are severe, this is a known ri sk of vaccines to healthcare
professionals with negligible public health impact.
a. Please note that CT dataset from the safety database includes only cases reporting SAEs.
b. Updated search criteria starting from the 6th SMSR (see 5th Monthly Safety Update preliminary PRAC
Assessment Report; EMEA/H/C/005735/MEA/002.4): PTs Anaphylactic reaction, Anaphylactic shock,
Anaphylactoid reaction, Anaphylactoid shock, without Brighton Collaboration criteria applied.
Important Potential Risks
Table 36. Vaccine -Associated Enhanced Disease (VAED), including Vaccine -
Associated Enhanced Respiratory Disease (VAERD)
Potential
mechanisms,
evidence source
and strength of
evidence This potential risk is theoretical because it has not been described in association with
the BNT162b2 or it has not been reported from any other late phase clinical trial of
other human vaccine. Animal models of SARS -CoV -2 infection have not shown
evidence of VAED after immunization, whereas cellular immunopathology has been
demonstrated after viral challenge in some animal models administered SARS -CoV -1
(murine, ferret and non -human primate models) or MERS -CoV (mice m odel)
vaccines .1,6 This potential risk has been included based on these animal data with
these related betacoronaviruses. Historically, diseas e enhancement in vaccinated
children following infection with natural virus has been observed with an inactivated
respiratory syncytial virus vaccine.7
Potential mechanisms of enhanced disease may include both T cell -mediated [an
immunopathological respon se favoring T helper cell type 2 (T H2) over T helper cell
type 1 (T H1)] and antibody -mediated activity (antibody responses with insufficient
neutralizing activity leading to formation of immune complexes and activation of
complement or allowing for Fc -medi ated increase in viral entry to cells).8
Characterization
of the risk
Participant 16 years and older
Data from the CT database (cut-off date 13 March 2021)
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Table 36. Vaccine -Associated Enhanced Disease (VAED), including Vaccine -
Associated Enhanced Respiratory Disease (VAERD)
Confirmed Case of Postvaccination Severe COVID -19 – Blinded Placebo -
Controlled Follow -up Period - Safety Population (C4591001)
BNT162b2 (30 μg)
(Na=23164) Placebo
(Na=23155)
Timing nb (%) (95% CIc) nb (%) (95% CIc)
PD1 Before Dose
2 0 (0.0, 0.0) 6 (0.0) (0.0, 0.1)
Within 7 days
PD1 0 (0.0, 0.0) 0 (0.0, 0.0)
PD2 1 (0.0) (0.0, 0.0) 25 (0 1) (0.1, 0.2)
Within 7 days
PD2 0 (0.0, 0.0) 2 (0.0) (0.0, 0.0)
Totald 1 (0.0) (0.0, 0.0) 31 (0 1) (0.1, 0.2)
Note: This table includes subjects from Phase 2/3 only
Abbreviations: PD1 = post -dose 1; PD2 = post -dose 2
a N = number of subjects in the specified group This value is the denominator for the
percentage calculations
b n = Number of subjects reporting at least 1 occurrence of the specified event
c Exact 2 -sided CI based on the Clopper and Pearson method
d Total is the sum of PD1 and PD2
PFIZER CONFIDENTIAL SDTM Creation: 25MAR2021 (23:24) Source Data:
adc19ef Table Generation: 27MAR2021 (12:47) (Cutoff date: 13MAR2021, Snapshot Date:
25MAR2021)
Output File: /nda2 unblind ed/C4591001 PVP BLA/adeff s901
If VAED/VAERD were to occur in vaccinated individuals, it may manifest as a
modified and/or more severe clinical presentation of SARS -CoV -2 viral infection
upon subsequent natural infection. This may result in individuals assumed to be at
lower risk for severe COVID -19 having more severe disease, for individuals at known
risk for severe COVID -19 (e.g. older or immunocompromised) having higher rates of
fatal outcomes, or for observation of an unfavorable imbalance in severe COVID -19
cases in vaccinated individuals when compared to those not vaccinated. It is
challenging to assess for VAED/VAERD on an individual case basis, given the lack of
specific clinical or laboratory markers at this time, rather surveillance for this
theoretical risk is best performed at a populati on level,9 as noted above. The table
above shows a favorable balance of severe COVID -19 cases in participants receiving
BNT162b2 versus those receiving placebo, providing reassurance against the potential
risk of VAED/VAERD at this time.
Data from the C T dataseta: (cut-off date 18 June 2021) :
There were no cases indicative of VAED/VAERD as SAEs in the CT dataset through
the DLP of 1 8 June 2021 .a.
Data from the safety database (cut-off date 18 June 2021)
No post-authorized AE reports have been identified as cases of VAED/VAERD,
therefore, t here is no observed d ata at this time. An expected rate of VAED is
difficult to establish so a meaningful observed/expected analysis cannot be conducted
at this point base d on available data. The feasibility of conducting such an analysis
will be re -evaluated on an ongoing basis as data on the virus grows and the vaccine
safety data continues to accrue.
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Table 36. Vaccine -Associated Enhanced Disease (VAED), including Vaccine -
Associated Enhanced Respiratory Disease (VAERD)
The search criteria utilised to identify potential cases of VAED for this report includes
PTs indicating a lack of effect of the vaccine and PTs potentially indicative of severe
or atypical COVID -19a..
Since the first temporary authorization for emergency supply under Regulation 174 in
the UK (01 December 2020) and through the DLP 18 June 2021, there were 584 cases
(0.2% of the total post -authorization dataset), reporting 1427 potentially relevant
events.
Seriousness criteria for the total 584 cases: Medically significant (452, of which 10
also serious for disability), Hospitalization required (non -fatal/non -life threatening)
(115, of which 3 also serious for disability), Life t hreatening (34, of which 22 were
also serious for hospitalization), Death (160).
Gender: Females (298), Males (268), Unknown (18);
Age (n=553) ranged from 17 to 103 years (mean = 70.3 years, median = 77.0);
Overall event seriousness and outcome are summarized below:
Total Events
N = 1427 (%)
Serious events 1261 (88.4)
Events with Criterion of
Hospitalization 612 (42.9)
Distribution of events by Outcome *
Outcome: Death 311 (21.8)
Outcome: Resolved/Resolving 375 (26.3)
Outcome: Not resolved 246 (17.2)
Outcome: Resolved with sequelae 14 (1.0)
Outcome: Unknown/No data 484 (33.9)
* For the outcome count, the multiple Lowest Level Terms that code to the
same PT within a case are counted and presented individually. Therefore, for
selected PTs the total count of the event outcome may exceed the total
number of events.
The most frequ ently reported relevant PTs ( ≥2% ) were: Drug ineffective ( 390),
Vaccination failure (194), Dyspnoea ( 180), COVID -19 pneumonia ( 179), Diarrhoea
(111), Respiratory failure (52), Vomiting ( 50), Pulmonary embolism (33).
Conclusion: VAED may present as severe or unusual clinical manifestations of
COVID -19. Overall, there were 425 subjects with confirmed COVID 19 following
one or both doses of the vaccine; 288 of the 425 cases were severe, resulting in
hospitalization, disability, life thr eatening consequences or death. None of the 288
cases could be definitively considered as VAED/VAERD.
In this review of subjects with COVID -19 following vaccination, based on the current
evidence, VAED/VAERVAED remains a theoretical risk for the vaccine.
Surveillance will continue.
Participants 12 to 15 years of age
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Table 36. Vaccine -Associated Enhanced Disease (VAED), including Vaccine -
Associated Enhanced Respiratory Disease (VAERD)
Data from the CT dataset database (cut-off date 02 September 2021) :
There were no cases reporting VAED/VAERD as SAEs in the CT dataset database
through the DLP of 18 June 02 September 2021 ..
Data from the safety database :b (cut-off date 30 September 2021) :
Through the DLP 18 June 30 September 2021, there were no cases 2 cases (reporting
6 potentially relevant events) indicative of VAED or VAERD in the safety database
involving individuals 12 to 15 years of age .a.
Booster Group
Data from the CT database:
No AEs were Seriousness criteria for the 2 cases: Life threatening (1 also serious for
hospitalization) and Hospitalization required (non -fatal/non -life threatening) (1).
Gender: Males (2) ;
Age (n=2): 12 years and 15 years (1 case each) ;
Overall event seriousness and outcome are summarized below:
Total Events
N = 6
Serious events 6
Events with Criterion of
Hospitalization 6
Distribution of events by Outcome
Outcome: Death 0
Outcome: Resolved/Resolving 4
Outcome: Unknown/No data 2
The relevant PTs reported that suggested any potential cases of severe COVID 19
among participants in the Phase 3 BNT162b2 booster group , from dose 3 to the d ata
cut-off date (17 June 2021).
Data from the safety database:
Through DLP 18 June 2021, no these 2 cases were retrieved reporting severe COVID -
19 : Diarrhoea , Drug ineffective, Multisystem inflammatory syndrome in the subjects
who received booster dose. children, Seizure, Vaccination failure, and Vomiting (1
each).
Conclusion: VAED may present as severe or unusual clinical manifestations of
COVID -19. In both cases, the subjects had confirmed COVID -19 following 2 doses of
the vaccine. Upon review, t hese 2 cases unlikely represent VAED as the clinical
course was not descriptive of an unusual clinical manifestation of COVID -19
infection .
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Table 36. Vaccine -Associated Enhanced Disease (VAED), including Vaccine -
Associated Enhanced Respiratory Disease (VAERD)
In this review of subjects with COVID -19 following vaccination, based on the current
evidence, VAED/VAERD remains a theoretical risk for the vaccine. Su rveillance will
continue.
Risk factors and
risk groups It is postulated that the potential risk may be increased in individuals producing lower
neutralizing antibody titers or in those demonstrating waning immunity.8,9
Preventability An effective vaccine against COVID -19 that produces high neutralizing titers and a
TH1 predominant CD4+ T cell response and strong CD8+ T cell response, is expected
to mitigate the risk of VAED/VAERD;1,8 that immune profile is elicited by BNT162b2
in clinical and preclinical studies.10,11
Impact on the
risk-benefit
balance of the
biologic product If there were an unfavorable balance in COVID -19 cases, including severe cases, in
the pivotal clinical study between the vaccine and placebo groups, that may signal
VAED/VAERD.
Public health
impact The potential risk of VAED/VAERD could have a public health impact if large
populations of individuals are affected.
a. Please note that CT dataset from the safety database includes only cases reporting SAEs. a.
b. Search criteria updated to include new PTs introduced in the MedDRA version 24.0. The updated searc h
criteria is: PTs Vaccine associated enhanced disease OR Vaccine associated enhanced respiratory disease OR
Standard Decreased Therapeutic Response Search AND at least 1 of the following PTs Dyspnoea;
Tachypnoea; Hypoxia; COVID 19 pneumonia; Respiratory F ailure; Acute Respiratory Distress Syndrome;
Cardiac Failure; Cardiogenic shock; Acute myocardial infarction; Arrhythmia; Myocarditis; Vomiting;
Diarrhoea; Abdominal pain; Jaundice; Acute hepatic failure; Deep vein thrombosis; Pulmonary embolism;
Periphera l Ischaemia; Vasculitis; Shock; Acute kidney injury; Renal failure; Altered state of consciousness;
Seizure; Encephalopathy; Meningitis; Cerebrovascular accident; Thrombocytopenia; Disseminated
intravascular coagulation; Chillblains; Erythema multiforme; M ultiple organ dysfunction syndrome;
Multisystem inflammatory syndrome in children. Note: the “Standard Decreased Therapeutic Response”
search includes the Lack of efficacy PTs (Drug ineffective/Vaccination failure). a. Please note that CT dataset
from the safety database includes only cases reporting SAEs.
2.1.2.c.2.2. Presentation of Missing Information
Table 37. Use in Pregnancy and Lactation
Evidence source:
The safety profile of the vaccine is not known in pregnant or lactating women due to their exclusion from the
pivotal clinical study. There may be pregnant women who choose to be vaccinated despite the lack of safety
data. It will be important to follow these women for pregnancy and birth outcomes. The timing of
vaccination in a pregnant woman and the subsequent immune response may have varying favorable or
unfavorable impacts on the embryo/fetus. The clinical consequences of SARS -CoV -2 infection to the
woman and fetus during pregnancy is not yet fully understood and the pregnant woman’s baseline health
status may affect both the clinical course of her pregnancy and the severity of COVID -19 disease. These
factors and the extent to which the pregnant woman may be at risk of exposure to SARS -CoV -2 will
influence the benefit risk considerations for use of the vaccine.
Population in need of further characterization:
The lack of data will be is communicated in product labeling; one clinical study of the safety and
immuno genicity of the BNT162b2 in pregnant and lactating women is ongoing (C4591015); 42 non-
interventional studies (C4591009 , and C4591011 , ) are planned and 2 non -interventi onal studies (C4591021,
and C4591022 ) are ongoing to assess whether subcohorts use of interest, such as pregnant women,
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Table 37. Use in Pregnancy and Lactation
experience increased risk of safety events of interest following receipt of the BNT162b2 are
planned /ongoing in pregnancy (see 3 1.3 – Action plan for safety issues ).
Data from the Safety Databasea (Cut-off date 18 June 2021 )
Since the first temporary authorization for emergency supply under Regulation 174 in the UK
(01 December 2020) and through 18 June 2021, there were 2636 cases ( 0.8 % of the total P ost-authorization
dataset) reporting use during pregnancy or lactation .
Overall event seriousness and outcome are summarized below:
Total Events
N = 6215 (%)
Serious events 2464 (39.6)
Events with Criterion of Hospitalization 314 (5 1)
Distribution of events by Outcome *
Outcome: Death 61 (1)
Outcome: Resolved/Resolving 1657 (26.7)
Outcome: Not resolved 602 (9.7)
Outcome: Resolved with sequelae 65 (1)
Outcome: Unknown/No data 3864 (62.2)
* For the outcome count, the multiple Lowest Level Terms that code to the same PT within a case are counted and
presented individually Therefore, for selected PTs the total count of the event outcome may exceed the total number
of events
The most frequently reported relevant PTs (≥2%) were: Maternal exposure during pregnancy (867),
Exposure via breast milk (791), Exposure during pregnancy (402), Off label use (296), Abortion
spontaneous, Product use issue (277 each), Headache (184), Matern al exposure during breast feeding (161),
Fatigue (155), Pyrexia (134), Pain in extremity (119), Vaccination site pain (91), Myalgia (79), Chills (75),
Maternal exposure timing unspecified (73), Nausea, Pain (72 each), and Dizziness (56).
Participants 1 2 to 15 years of age
Data from the safety database : (Cut-off date 30 September 2021)
Through 30 September 2021, there was 1 case reporting use of BNT162b2 during pregnancy in the safety
database. The serious case involved a 12 -year-old female who received first dose of BNT162b2 during
pregnancy (trimester of exposure unknown) and had miscarriage after 2 weeks of vaccine administration
(PTs Maternal exposure during pregnancy, Fatigue, and Abortion spontaneous). Patient outcome was
reported as recovered with sequelae. Through 30 September 2021, there were no cases reporting use of
BNT162b2 during lactation.
a. Cumulative RMP tables on Missing information are provided as pe r previous FDA’s request to include a
cumulative analysis, from post -authorization experience, of the Important Missing Information identified in
the Pharmacovigilance Plan.
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Table 38. Vaccine Effectiveness
Evidence source:
Although vaccine efficacy in a controlled clinical stud y is the objective of the pivotal stud y, real -world
vaccine effectiveness when the BNT162b2 is used in a large and more diverse population is unknown.
Anticipated risk/consequence of missing in formation:
Efficacy information obtained from clinical study data will be is communicated in the product labeling. Four
post-authorization effectiveness studies in real -world use are planned /ongoing : 1 interventional study
(BNT162 -01 cohort 13), 1 non -interventional study (C4591014) and 2 low -interventional studies (WI235284
and WI255886) to determine the effectiveness of BNT162b2 when administered outside of the clinical
setting (see 3.1.3 – Action plan for safety issues ).
Data from the Safety Databasea (Cut-off date: 18 June 2021)
Since the first temporary authorization for emergency supply under Regulation 174 in the UK
(01 December 2020) and through 18 June 2021, there were 6373 cases ( 1.9% of the total P ost-authorization
dataset) reporting lack of efficacy .
Overall event seriousness and outcome are summarized below:
Total Events
N = 6373 (%)
Serious events 6373 (100)*
Events with Criterion of Hospitalization 616 (9.7)
Distribution of events by Outcome
Outcome: Death 334 (52)
Outcome: Resolved/Resolving 1253 (19.7)
Outcome: Not resolved 721 (11.3)
Outcome: Resolved with sequelae 21 (0.3)
Outcome: Unknown/No data 4044 (63.5)
*Includes 26 cases where LOE was captured as non -serious and upgraded to serious after the DLP.
The PT Drug ineffective was reported in 4765 cases, Vaccination failure was reported in 1608 cases; t he
most frequently co-reported PTs (≥2%) were: COVID -19 (5022), Asymptomatic COVID -19 (502), Pyrexia
(412), Suspected COVID -19 (379), SARS -CoV -2 test positive (359), Headache (327), Fatigue (262), Cough
(227), Dyspnoea (180), COVID -19 pneumonia (179), Myalgia (162), Asthenia (156), Malaise (152), and
Chills (133) .
Participants 1 2 to 15 years of age
Data from the safety database : (Cut-off date 30 September 2021)
Through 30 September 2021, there were 2 9 cases retrieved reporting lack of efficacy . Upon review, 1 case
was not considered to be true lack of efficacy because the subject developed SARS -CoV -2 infection during
the early days from the first dose (days 1 -13); the development of a vaccine preventable disease during this
time is not considered a lack of effect of the vaccine. Therefore, there wer e 28 relevant cases reporting lack
of efficacy in individuals 12 to 15 years of age; overall event seriousness and outcome are summarized
below:
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Table 38. Vaccine Effectiveness
Total Events
N = 28 (%)
Serious events 28 (100)
Events with Criterion of Hospitalization 2 (7.1)
Distribution of events by Outcome
Outcome: Death 0
Outcome: Resolved/Resolving 4 (14.3)
Outcome: Not resolved 1 (3.6)
Outcome: Unknown/No data 23 (82 1)
The PT s Drug ineffective and Vaccination failure were reported in 19 and 9 cases , respectively ; the
co-reported events reported more than once were coded to the PTs : COVID -19 (24), Pyrexia (5),
Headache (4), Suspected COVID -19 (3), and Fatigue (2).
a. Cumulative RMP tables on Missing information are provided as per previous FDA’s request to include a
cumulative analysis, from post -authorization experience, of the Important Missing I nformation identified in
the Pharmacovigilance Plan.
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Table 39. Use in Paediatric Individuals <125 Years of Age§
Evidence source :
BNT162b2 has not been initially studied in pediatric individuals younger than 12 years of age due to their
exclusion from the pivotal clinical study .
Paediatric individuals may display different reactogenicity and safety profiles compared to adults, due to
lower body mass and differently matured immunological responses.
Population in need of f urther characterization :
The are no data in individuals less than 125 years of age ; ain the pediatric population:
• 3 clinical studies [C4591001 ( ≥12 to ≤15 years of age), C4591007 (<12 years of age) and C4591007
substudy - Troponin group (5 to <12 years of age and 12 to <1 6 years of age ) are ongoing;
• 1 clinical study of the safety, tolerability, immunogenicity and efficacy of BNT162b2 in individual s
younger than 12 years [C4591007 (< 12 years of age)]a is ongoing (see 3.1.3 – Action plan for safety
issues ); a[C4591023 (<6 months; ≥5 to <12 years of age) is planned;
• 2 non-interventional study ( studies [ C4591009 ) is planned to assess the occurrence of safety events
of interest in a general US population (< 12 and ≥ 12 to ≤15 years of age) (see 3.1.3 – Action plan
for safety issues ); a non -interventional study ( and C4591038 (former C4591021 ) to assess potential
increased risk of AESI, in a general EU population substudy) (<12 years of age)] are planned;
• 1 low interventional study is planned [C4591036 (<21 years of age , including <12 years is ongoing
(of age)]
For details on these studies, see 3.1.3 – Action plan for safety issues ); a non -interventional study (C4591036)
to characterize the clinical course, risk factors, long term sequelae, and quality of life in children and young
adults <21 years with acute post vaccine myocarditis/pericarditis is planned (see 3.1.3 Action plan for
safety issues )..
Data from the Safety DatabasebDatabas ea (cut-off date 30 September 2021)
Since the first temporary authorization for emergency supply under Regulation 174 in the UK
(01 December 2020) and through 18 June 30 Sept ember 2021, there were 132 cases 56 casesb (0.0401% of the
total P ost-authorization dataset) involving indivi duals below 125 years of age .
Overall event seriousness and outcome are summarized below:
Total Events
N = 343172 (%)
Serious events 34 (9.930 (17.4)
Events with Criterion of Hospitalization 3 (1 (0.3.7)
Distribution of events by Outcome *
Outcome: Death 2 (0.61 2)
Outcome: Resolved/Resolving 101 (29.461 (35.5)
Outcome: Not resolved 53 (15.546 (26.7)
Outcome: Resolved with sequelae 0
Outcome: Unknown/No data 192 (56.063 (36.6)
* For the outcome count, the multiple Lowest Level Terms that code to the same PT within a case are
counted and presented individually. Therefore, for selected PTs the total count of the event outcome may
exceed the total number of events.
The most frequently reported PTs (≥2%) (3 occurrences ) were: Product administered to patient of
inappropriate age ( 4321), Off label use ( 3717), Product use issue ( 2615), Pyrexia ( 1311), Fatigue, Headache
(11 each), Pain in extremity (10), Nausea (8), Malaise , Myalgia (7 each), Arthralgia, Dizziness, Pain (6
each), Chills, Swelling (5 each), Diarrhoea, Pruritus, Rash ( , and Nausea (4 each), Abdominal pain upper,
Circumstance or information capable of leadi ng to medication error, Cough, Injection site pain,
Nasopharyngitis, Peripheral swelling, Vaccination site pain, Vaccination site swelling, and Vomiting (3
each). ).
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a. Phase 1 open label dose -finding study to evaluate safety, tolerability, and immunogenicity and phase 2/3
placebo -controlled, observer blinded safety, tolerability, and immunogenicity, study of a SARS -CoV -2 RNA
vaccine candidate against COVID 19 in healthy children <12 years of age.
b.§ Missing information has been reworded to reflect the current state .
a. Cumulative RMP tables on Missing information are provided as per previous FDA’s request to include a
cumulative analysis, from post -authorization experience, of the Important Missing Information identified in
the Pharmacovigilance Plan ...
b. Please note that at the DLP of 18 June 2021 there were 29 additional pediatric cases under 5 years of
age; at the DLP of 30 September 2021, follow -up information was received for these cases and they were
identified to refer to adult subjects, rather than to pediatric subjects under 5 year s of age.
2.1.2.d. Identified and Potential Interactions , Including Food -Biologic Product and
Drug -Biologic Product Interactions
As noted in the WHO Guidelines on Nonclinical Evaluation of Vaccines,3 pharmacokinetics
testing is n ot required for final formulation. No interaction linked to metabolism is expected
with vaccines. The only potential for interaction is with other vaccines administered
concomitantly and with immunosuppressive drugs.
Co-administration studies with BNT162b2 have not been done , therefore th ere is not
sufficient data to understand the effect o n vaccine effectiveness of BNT162b2 or co-
administered vaccines. A co -administration study with seasonal influenza vaccine is
planned. If BNT162b2 is given at the same time as other injectable vaccine(s), the vaccine(s)
should be administered at different injection sites.
2.1.2.e. Epidemiology of Indication and Target Population
Indication
Active immunization against to prevent COVID -19 disease caused by SARS -CoV -2 virus , in
individuals ≥ 1612 years of age and older .
Incidence:
The COVID -19 is caused by a novel coronavirus labeled as SARS -CoV -2. The disease first
emerged in December 2019, when a cluster of patients with pneumonia of unknown cause
was recognized in Wuhan City, Hubei Province, China .12 The number of infected cases
rapidly increased and spread beyond China throughout the world. On 30 January 2020, t he
WHO declared COVID -19 a Public Health Emergency of International Concern and thus a
pandemic.13
Estimates of SARS -CoV -2 incidence change rapidly. WeThe MAH obtained incidence and
prevalence estimates using data from Worldometer, a trusted independent organization that
collects COVID -19 data from official reports and publishes current global and
country -specific statistics online.14
As of 03 March 15 August 2021 , the overall number of people who had been infected with
SARS -CoV -2 was over 115207 million worldwide,15 an increase of nearly 100 92 million in
the 75 months since 28 July 2020 03 March 2021 .16 Table 35Table 40 shows the incidence
and prevalence as of 03 March 15 August 2021 for the US, UK, and EU -27 count ries. In the
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the EU and UK on 03 March 2021.16 The range of reported prevalence was 8115 to
6,019 1,544 per 100,000: Croatia, Denmark Slovakia, Romania , and Germany Czech Republic
reported the lowest prevalence while Belgium, France Spain, Cyprus, and Ireland Finland
reported the highest ( Table 40).
In the US, the prevalence on 03 March 15 August 2021 was nearly twice as high as similar to
the combined EU+ UK estimates , with 2,685 1,997 active cases per 100,000.1515 The
prevalence in the US was 653 This is a decrease of approximately 700 per 100,000 on 28 July
2020 since 03 March 2021, when the prevalence was 2,685 per 100,000 .1616
Demographics of the population in the proposed indication and risk factors for the
disease:
Since the beginning of the pandemic, the ECDC has continuously collected COVID -19
information from all countries who are members of the EU/EEA and the UK . In the ECDC’s
TESSy database, COVID -19 case -based data, including age and gender, are available for
over 80% of the official number of cases repo rted by ECDC epidemic intelligence,19 enabling
estimates of age and gender distribution representative of the European population. TESSy
data on age and sex distributions by severity of symptoms as posted on 04 March 12 August
2021 are shown in Figure 1.20
The top half of the figure represents data ending on 31 July 2020 and the bottom half
presents data from 01 August 2020 to 04 March 08 August 2021 (Figure 1). In general, the
age-sex patterns before 01 August 2020 have remained the same since then. The gender
distribution of persons testing positive for SARS -CoV-2 in the European population is
similar for most age groups. Cases reported in TESSy have been older than the general
population throughout the pandemic , with few cases observed in people aged younger than
20 years. This likely reflects the age distribution of people who met the requirements for
being tested and is unlikely to reflect the actual distribution of infections in the population.
Those with severe outcomes (hospitalized, severely hospitalized , [admitted to intensive care
and/or re quired respiratory support] , or fatal) have been disproportionately older and male
compared to COVID -19 cases overall. While age -sex patterns have remained consistent
throughout the pandemic, a notable difference between the periods before and since 01
August 2020 is that the absolute numbers of cases have increased dramatically in the latter
period compared to the earlier one.
Figure 1. Age-Sex distribution of COVID -19 Cases as Different Levels of Severity,
Pooled Data for EU/EEA and UK Countries . Case -based Data from TESSy
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produced on
04 March 12 August 2021a
Note: ”“mild”=” = a case that has not been reported as hospitalized or a case that resulted in death
a Data from ECDC COVID -19 Surveillance report Week 831, 2021 4 March 12 August 2021 “2 2 Age -sex pyramids”
Accessed 6 March 15 August 202120
US distributions of COVID cases and deaths by age, sex, and race, as well as the
cross -tabulation of age and sex, are shown in Table 36.21 Table 41 as of 14 August 2021 .22
At that time, the CDC reported that the US had recorded a total of 36,556,516 cases of
COVID and 618,591 deaths attributable to the disease. However, because demographic data
were not available for all US COVID cases and deaths, the numbers in Table 41 and Table 42
are drawn, respectively, from 29,346,352 cases and 513,204 deaths. Those under age 50
account for 65roughly 67% of cases but less than approximately 5% of deaths. For ages 18 -
74, males account for less than half of cases but over 60% of deaths. Among the pediatric
population, there is close to a 50 -50 case distribution bet ween males and females across ages
0-17. However, the pediatric mortality distribution is highly irregular between the sexes,
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with males being 51.5% of COVID deaths among 0 -4 year olds, 55.9% among 5 -11 year
olds, 46.7% among 12 -15 year olds, and 68.7% am ong 16 -17 year olds.
Table 41. Distributions Distribution of Cases (n= 21,895,936) and Deaths
(n=382,009 29,346,352 ) by Age, Sex, Race, and Cross -Tabulated Age and
Sex -- United States as of
08 March 14 August 202121,aa 22
Age x Sex %
Event Age
Grou
p Age
% Sex Sex
% RacebRaceb Race % Age
Grou
p Males % Females
%
Cases 0-4 2.2 Males 47.8
7 H/L 20.7 28.
3 0-4 51.7 48.3
5-
1711 9.54.
2 Female
s 52.2
3 AI/AN 1.2 5-
1711 4950.8 50.2 49.
1
12-15 3.8 Asian 3.2 12-15 49.6 50.4
16-17 2.6 Black 11.6 16-17 48.3 51.7
18-29 22.47 NH/PI Asian 0.3.6 18-29 47.1 46.
9 52.9 53.
1
30-39 16.36 White Blac
k 12.2 50.
3 30-39 48.2 47.
9 51.8 52.
1
40-49 14.98 M/O NH/PI 0.45.3 40-49 47.7 52.3
50-64 20.5 White 56 50-64 48.56 51.54
65-74 7.83 M/O 6 65-74 4948.7 51.3
75-84 4.13.
7 75-84 45.7 54.3
85+ 2.41 85+ 33.9 34.
4 66.1 65.
6
Death
s 04 <0.1 Males 54.3 H/L 12.2 04 47.6 52.4
517 0.1 Female
s 45.7 AI/AN 1 517 57.7 42.3
1829 0.5 Asian 4.3 1829 63 37
3039 1.1 Black 14.7 3039 66 34
4049 2.8 NH/PI 0.2 4049 66 5 33.5
5064 14.5 White 63.1 5064 65 35
6574 21.3 M/O 4.4 6574 61.4 38.6
7584 27.7 7584 55.8 44.2
85+ 32.1 85+ 41.8 58.2
a. Percentage of missing demographic data varied by types of event and demographic.
b. Except for Hispanics/Latinos, all categories refer to non -Hispanics
Abbreviations: AI/AN=American Indian/Alaska Native, H/L=Hispanic/Latino, M/O=Multiple/Other,
NH/PI=Native Hawaiian/Other Pacific Islander
Table 42. Distribution of Deaths (n=513,204) by Age, Sex, Race, and
Cross -Tabulated Age and Sex -- United States as of 14 August 2021a 22
Event Age
Group Age % Sex Sex % Raceb Race
% Age
Group Males
% Females
%
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Deaths 0-4 <0 1 Males 54.2 H/L 18.5 0-4 51.5 48.5
5-11 <0 1 Females 45.8 AI/AN 1 2 5-11 55.9 44.1
12-15 <0 1 Asian 3.8 12-15 46.7 53.3
16-17 <0 1 Black 13.8 16-17 68.7 31.3
18-29 0.6 NH/PI 0 2 18-29 64 36
30-39 1.3 White 58.7 30-39 65.1 34.9
40-49 3.1 M/O 3.8 40-49 65.3 34.7
50-64 15.4 50-64 64 36
65-74 21.6 65-74 60.6 39.4
75-84 27.3 75-84 55.5 44.5
85+ 30.7 85+ 41.8 58.2
a. Percentage of missing demographic data varied by types of event and demographic
b. Except for Hispanics/Latinos, all categories refer to non -Hispanics
Abbreviations: AI/AN=American Indian/Alaska Native, H/L=Hispanic/Latino, M/O=Multiple/Other, NH/PI=Native
Hawaiian/Other Pacific Islander
In general, d isease has been much less severe among ages 0 -24 compared to ages ≥25 years ,
with 2.5% hospitalized, 0.8% admitted to an intensive care unit, and <0.1% dying among
ages 0 -24, versus 16.6% hospitalized, 8.6% in tensive care, and 5% dying among ages
≥25 years .23 Among hospitalized cases with COVID -19 in the US, approximately 90% are
over 40 years old, and between 58% to 66% are at least 60 years old.24 The majority
(approximately 60%) of COVID -19 patients admitted to hospitals in the US have been
male.24,25,26,27,28
African American COVID -19 patients have been reported to have an increased risk of
hospitalization25,29 and mortality,30 compared to white patients in the United States. A CDC
report examined demographic trends among US COVID -19 deaths from May to August of
2020.31 During the observation period, the percentage of US COVID -19 deaths that were
Hispanic increased from 16.3% i n May to 26.4% in August, the only racial or ethnic group
among whom the percentage of deaths increased during that time. In terms of setting, 64.3%
of deaths occurred in inpatient hospitals and 21.5% in nursing homes or long -term care
facilities.
As of 0 8 March 2021, the CDC estimated that The most recent CDC estimate of the total
number of excess deaths (as opposed to overall deaths in the preceding paragraph) across the
US from 0126 January 2020 to 27 February 2020 to the present 2021 from all causes
(COVID -19 and otherwise) ranged from 509,890 624,307.32 A CDC report examining US
545,600 -660,200, with an estimated 75 -88% of excess deaths being associated with race and
age, restricted to the period 26 January 2020 to 03 October 2020, estimated that 66% of
USCOVID -19.33 An earlier CDC report on excess deaths covering 26 January 2020 through
3 October 2020 broke down excess deaths by demographics33: by age during that period were
attributable to COVID 19.34 By age , the largest increase in deaths compared to average
expected deaths occurred among adults aged 25 -44 (26.5% increase). By race, increases in
deaths compared to expectation were largest among Hispanics (53.6% increase), Asian
Americans (36.6% increase), African Americans (32.9% increase), and Native Americans
and Native Alaskans (28.9% increase), all compared to an excess 11.9% deaths among non -
Hispanic whites.
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While research earl ier in the pandemic tended to focus on adults, more recent data have given
greater attention to children and adolescents. For the period January 1 -March 31 2021 across
14 states (the most recently available data), the CDC’s COVID -NET database recorded 204
adolescents aged 12 -17 who were hospitalized for likely primarily COVID -19-related
reasons.35 The 204 adolescents were 47.5% male —consistent with the COVID case sex
distribution across all ages —and disproportionately from minorities, with 31.4% Hispanic
and 35.8% non -Hispanic African Americans.35
Another recent CDC report described demographic trends in US COVID -19 incidence
among 15,068 cases aged 0 -24 years across 16 jurisdictions during the period 01 January
2020 through 31 December 2020.36 The report broke down incidence by age groups and
2020 sub -periods that are presented in Table 43. The table shows that early in 2020, 5 -9 year
olds were experiencing less COVID -19 than 0 -4 year olds, but by the end of the year this
pattern had reversed. Compared to 5 -9 year olds, the age categories 10 -14, 15 -19, and 20 -24
years old showed progressiv ely greater incidence rates, a pattern that held throughout 2020.
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Table 43. COVID -19 incidence and rate ratios, by age group among persons aged
<25 years across three periods of 2020 in 16 U.S. jurisdictions36
2020
Sub-Period Age Group
(years) Number
of Cases Cases per 100,000 population
(95% CI) Rate Ratio
(95% CI)
Jan 1 -Apr 30 0-4 956 21 (20 -23) 1.28 (1.17 -1.41)
5-9 772 17 (16 -18) Referencea
10-14 1,184 25 (23 -26) 1.49 (1.36 -1.63)
15-19 3,267 67 (65 -70) 4.03 (3.72 -4 36)
20-24 8,889 175 (171 -178) 10.47 (9.72 -11.26)
May 1 -Aug 31 0-4 14,017 314 (309-319) 1.01 (0.98 –1.03)
5-9 14,406 312 (307 -317) Referencea
10-14 20,490 430 (424 -436) 1.38 (1.35 –1.41)
15-19 50,210 1,034 (1,025 -1,043) 3.32 (3.26 –3.38)
20-24 78,655 1,547 (1,536 -1,557) 4.96 (4.88 –5.05)
Sep 1 -Dec 31 0-4 33,595 752 (744 –760) 0.71 (0.70 –0.72)
5-9 48,824 1,056 (1,047 –1,066) Referencea
10-14 76,922 1,615 (1,604 –1,627) 1.53 (1.51 –1.55)
15-19 149,660 3,083 (3,067 –3,098) 2.92 (2.89 –2.95)
20-24 187,825 3,693 (3,677 –3,710) 3.50 (3.46 –3.53)
a Reference to imply that incidence rate in 5 -9 year -old age group is used as comparison to calculate rate ratios for
other age groups
Other US pediatric data are generally consistent with the CDC findings. Table 44
summarizes demographic results for a retrospective cohort of 135,794 individuals under the
age of 25 who were tested for COVID -19 by 08 September 2020 within the PEDSnet
network of US pediatric health systems.37 The Table 44 shows that, among the pediat ric
population, children age 12 -17 were more frequently infected than those under age 12.
African Americans and Hispanics had elevated frequencies of testing positive relative to their
proportion of the cohort.
A study of 1,945,831 individuals aged 0 -18 recorded in the Premier Healthcare Database
between March and October 2020 included 20,714 pediatric cases of COVID -19; the authors
reported similar patterns to what is shown in Table 43, with the additional observation that
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COVID -19 cases aged 0 -1 and 12 -18 years were more likely to develop serious illness than
those aged 2 -11.38
Table 44. Demographics of 135,794 US individuals under age 25 tested for
COVID -19 by 08 September 202037
Characteristic Patients, n (%)
COVID -19 negative
(n=130,420) COVID -19 positive,
Asymptomatic or mild
illness (n=5,015) COVID -19 pos itive,
Severe illness (n=359)
Age, years
<1 17,431 (13) 494 (10) 72 (20)
1-4 32,619 (25) 808 (16) 40 (11)
5-11 35,617 (27) 1,029 (21) 72 (20)
12-17 32,362 (25) 1,521 (30) 117 (33)
18-24 12,391 (10) 1,163 (23) 58 (16)
Sex
Female 61,637 (47) 2,527 (50) 172 (48)
Male 68,701 (53) 2,485 (50) 187 (52)
Other or Unknown 82 (0.06) 3 (0.06) 0
Race/ethnicity
Hispanic 14,156 (11) 918 (18) 108 (30)
API 4,471 (3) 151 (3) 9 (3)
Black or AA 18,646 (14) 1,424 (28) 119 (33)
White 77,540 (60) 1,988 (40) 97 (27)
Multiple 3,883 (3) 126 (3) 5 (1)
Other or Unknown 11,724 (9) 408 (8) 21 (6)
AA=African American, API=Asian or Pacific Islander
Risk Factors
While anyone can become infected with SARS -CoV -2, symptoms of COVID -19 disease can
range from very mild (or no symptoms) to severe or fatal. A person’s risk of initial infection
increases through spending time in close physical proximity to others, especially in indoor
spaces with poor ventilation.39 People living in long -term care facilities or high -density
apartment homes, or working in occupations with close proximity to others (e.g. healthcare,
transportation), have a higher risk of infection .33,40,. 39,41 Among children, the primary source
of infection is an infected adult living in the same household.42 According to the CDC,
people ages 18 29some ethnic minority groups have the highest a higher risk of infection, but
age is not associated with risk of initial infection , while children age 4 among people aged 5
and under have the lowest rate older (Table 37).43 Risk of infection is also higher among
some ethnic minority groups.,5Table 45).46, 47
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Table 45. Risk for COVID -19 Infection, Hospitalization infection, Hospitalisation , and
Death by Age Group 36 and by Race/Ethnicity 3747
Rate ratiosa
Age Group (years) Cases Casesc Hospitalization Hospitali sationd Death Deathe
0-4 <1 2<1 2<1
517 5-17 1 <1 <1
18-29 18-29b 31 71 151
30-39 21 102 454
40-49 21 152 13010
50-64 21 254 40035
65-74 21 356 1100 95
75-84 21 559 2800 230
85+ 21 8015 7900 600
Race/Ethnicity
Non-Hispanic White bf 1 1 1
American Indian or Alaska Native,
non-Hispanic 1.97 3.74 2.4
Asian, non -Hispanic 0.7 1.10 1.0
Black or African American, non -
Hispanic 1 1 2.98 1.92.0
Hispanic or Latino 1.39 3.2.8 2.3
aa. Rates are expressed as whole numbers, with values less than 10 rounded to the nearest integer, two -digit
numbers rounded to nearest multiple of five, and numbers greater than 100 rounded to two significant
digits.
b. Rate ratios for each age group are relative to the 5—1718-29-year age category. This group was sel ected
as the reference group because it has accounted for the largest cumulative number of COVID -19 cases
compared to other age groups.
bc. Includes all cases reported by state and territorial jurisdictions (accessed on July 12, 2021). The
denominators used to calculate rates were based on the 2019 Vintage population
(https ://www.census.gov/newsroom/press -releases/2019/popest -nation.html).
d. Includes all hospitalizations reported through COVID -NET (from March 1, 2020 through July 3, 2021,
accessed on July 1 2, 2021). Rates were standardized to the 2020 US standard COVID -NET catchment
population (https://www.cdc.gov/coronavirus/2019 -ncov/covid -data/covid -net/purpose -methods.html).
e. Includes all deaths in National Center for Health Statistics (NCHS) provisional death counts (accessed
on July 12, 2021). The denominators used to calculate rates were based on the 2019 Vintage population
(https://data.cdc.gov/NCHS/Provisional -COVID -19-Deaths -by-Sex-and-Age/9bhg -hcku).
f. Rate ratios for each race/ethnicity group are relative to the Non -Hispanic White category.
Risk for severe or fatal COVID -19 disease has been shown to increase with older age, male
sex, or ethnic minority status .36. 46,37,38,48,49,50 Risks47, 51 52, 53,54 Children aged 5 -17 typically
experience a milder disease course and have lower risk of hospitalization andor
death .46,55,56Among adults, these risks increase dramatically for every 10 -year age group
above age 1739 (Table 37Table 42).36,41 46, 57 Table 37Table 45 also gives estimated rate ratios
for COVID -19 hospitalization hospitali sation and death by race/ethnicity relative to white,
non-Hispanic persons in the US. The highest risks of hospitalizatio nhospitali sation and death
were observed among American Indian or Alaska native persons (RR = 3. 74 for
hospitalization hospitali sation and 2.4 for death) and Hispanic or Latino persons (RR = 3.2.8
for hospitalization hospitali sation and 2.3 for death). Thes e differences in risk among ethnic
groups may be attributed to differences in underlying factors that are correlated with
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race/ethnicity including socioeconomic status, access to health care, and occupation -related
virus exposure .3747
Risk of severe or fatal COVID -19 disease is higher among persons who are current or former
smokers, have lower socioeconomic status, have no or public insurance, or live in
neighborhoods with higher rates of limited English proficiency .38,40,41,58. 51,53,57 The CDC has
also recognized other socio -demographic groups who may need to take extra precautions
against COVID -19 due to increased risk for severe illness: pregnant women; breastfeeding
mothers; people with disabilities or developmental/behavioral disorders; people living in
rural communities, nursing homes, long term care facilities, or prisons; people experiencing
homelessness ; people with developmental , behavio ural, or substance abuse disorders ; and
newly resettled refugee populations.59
RiskAmong adults, r isk for severe or fatal COVID -19 disease also increases with the
presence of chronic medical conditions, including obesity, respiratory chronic lung diseases
(e.g., COPD or asthma), cardiovascular disease, diabetes, cancer, liver disease, neurologi cal
diseases (e.g., stroke or dementia), chronic kidney disease, sickle cell disease, autoimmune
conditions and immunosuppression, orHIV, higher scores on the WHO Clinical Progression
Scale and Charlson Comorbidity Index .38,39,40,41,4252, 57, 60, 51, 53. Table 38Table 46 shows the
estimated hazard ratios of COVID -19 mortality associated with these chronic conditions and
socio -demographics from a cohort study of 17 million adults in England.41(with 17,000
COVID -19-related deaths) in England.57
The presence of one or more underlying medical conditions also increases risk of severe or
fatal disease among children aged 5 -17.61,62,63, 64 In particular, childhood obesity has been
consistently associated with two to three times the risk of severe disease or hospitalization .61,
64, 65, 66,. For many other individual comorbid conditions, pediatric sample sizes are very small
and different studies produce conflicting results, so it is difficult to estimate precise risk
ratios based on current literature.42, 63
Table 46. Hazard Ratios and 95% Confidence Intervals for COVID -19-related
Death4157
Characteristic Category COVID -19 death Hazard Ratio
Adjusted for
age, sex, and sexNHS
administrative region Fully adjusted
Age 18-39 0 05 (0 04 -00706) 0 06 (0 04 -00807)
40-49 02832 (02328-03338) 03034 (025 29-
03639)
50-59 1 00 (ref) 1 00 (ref)
60-69 27993 (25269-31020) 24057 (21635-
26680)
70-79 9 17 ( 862 (7.84 48-
94693) 607 (5.51 -74
(66921-7 31)
80+ 38 29 (35.02 -
41.87) 43 16 (40 03 -
46 53) 20.60 (18.70 -24 10
(226823-26 13 )
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Table 46. Hazard Ratios and 95% Confidence Intervals for COVID -19-related
Death157
Characteristic Category COVID -19 death Hazard Ratio
Adjusted for
age, sex, and sexNHS
administrative region Fully adjusted
Sex Female 1 00 (ref) 1 00 (ref)
Male 17873 (17168-18578) 15955 (15350-
16560)
BMI (kg/m2) Not obese 1 00 (ref) 1 00 (ref)
30-34.9 (obese class I) 1 23 (1 1718-13028) 10507 (10003-
11112)
35-39.9 (obese class II) 18179 (1 68 –-19590) 14044 (130–36-
15254)
40+ (obese class III) 26676 (239–2 95 54-
3 00) 2 11 ( 192 (1.72 –
93-21329)
Smoking Never 1 00 (ref) 1 00 (ref)
Former 14344 (137–40-1 49) 11926 (114–22-
12430)
Current 11417 (105–10-
12325) 08997 (082–
0.97 91-1 04)
Ethnicity White 1 00 (ref) 1 00 (ref)
Mixed 16259 (1262.08 28-
1 97) 1 43 (1 1115-
18478)
South Asian 16997 (1541.84 82-
2 14) 14570 (13255-
15885)
Black 18882 (165–61-
21405) 14844 (129–27-
16963)
Other 13738 (113–17-
16563) 13338 (110–16-
16163)
IMD quintileea 1 (least deprived) 1 00 (ref) 1 00 (ref)
2 11617 (10811-1 23) 11213 (105–07-
1 19)
3 13137 (123–30-
14044) 12225 (115–19-
13032)
4 16977 (159–68-
17986) 15153 (142–46-
1 61)
5 (most deprived) 2 11 ( 1.98 22501-
2 22) 17971 (16862-
19180)
Blood pressure Normal 1 00 (ref) 1 00 (ref)
High BP or diagnosed
hypertension 1 09 (1 0506-11413) 08990 (08587-
09394)
Respiratory disease excluding asthma 1.95 (1.86 –2.04) 16366 (15559-
17173)
Asthmab (vs. none) With no recent OCS use 11315 (107–10-
12021) 1 00 ( 099 (0 93 –
95-1 05)
With recent OCS use 15561 (139–47-
17375) 11315 (101–05-
1 26)
Chronic heart disease 1.57 (1.51 –1.64) 1.17 (1.12 –1.22)
Diabetescb (vs. none) With HbA1c < 58 mmol/mol 15853 (151–47-
16659) 13120 (124–16-
13725)
With HbA1c ≥ 58 mmol/mol 26157 (246–45-
27770) 19583 (183–
2.08 74-1 93)
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Table 46. Hazard Ratios and 95% Confidence Intervals for COVID -19-related
Death157
Characteristic Category COVID -19 death Hazard Ratio
Adjusted for
age, sex, and sexNHS
administrative region Fully adjusted
With no recent HbA1c
measure 22719 (20602-
25037) 19071 (172
2.09 58-1 86)
Cancer (non -
hematological, vs none) Diagnosed <1 year ago 18147 (158–2.07 31-
1 65) 17244 (150–28-
19662)
Diagnosed 1 -4.9 years ago 12013 (110–04-
13222) 11511 (105–03-
12720)
Diagnosed ≥ 5 years ago 0 99 (0 93–95-10604) 0.96 (0.91 –2 41
(10386-3 13)
Hematological
malignancy (vs. none) Diagnosed <1 year ago 2 54 (1 96 -302 (2.24
4.08 29) 2 80 (2 08 –3 78)
Diagnosed 1 -4.9 years ago 256 (28 (1 95 -214
3.06 66) 246 (25 (1 92 -
206–2.95 62)
Diagnosed ≥ 5 years ago 17071 (14651-
19893) 16165 (13946-
1 87)
Reduced kidney
functiondc (vs. none) eGFR 30 -60 15650 (149–45-
16355) 13330 (128–25-
14035)
eGFR <15-< 30 3.48 (3.23 –3.75) 2 74
(2 56 -2 93) 2 52 (2 33 –2 72)
eGFR <15 or dialysis 6 40 (5 75 -7 12) 4 42 (3 93 -4 98)
Liver disease
23927 (206–01-
27757) 1 75 (1 51–2.03 54-
1 98)
Dementia 4 59 (4 33 -4 87) 3 62 (3 41 -3 84)
Stroke or dementia 257 (03 (1 95 -246–
2.70 12) 2.16 (2.06 –
2 27) 1 53 (1 46 -
1 59)
Other neurological disease 30815 (285–96-
33336) 25872 (238–55-
27990)
Organ transplant
6.00 5 54 (473
7.61 51-6 81) 3.53 ( 1 61 (1 28 -
2774.49 02)
Asplenia
16250 (1192 21 16-
1 95) 13426 (09897-
18364)
Rheumatoid arthritis, lupus, or psoriasis 1.30 (1.21 –1.38) 11923 (11117-
12730)
Other immunosuppressive condition 2.75 (2.10 –3.62) 22100 (168–57-
29054)
a. Ethnicity hazard ratios were estimated from a model restricted to those with recorded ethnicity.
b. For OCS use, ‘recent’ refer s to during the year before baseline.
ca. Classification by HbA1c is based on measurements the most recent measurement within 15 months of baseline
db. eGFR is measured in mlmL min−1 per 1.73 m2 and taken derived from the most recent serum creatinine
measurement.
ec. Index of Multiple Deprivation (derived from the patient’s postcode)
Models were adjusted for age using a four -knot cubic spline for age, except for estimation of age -group hazard ratios
Ref, reference group; 95% CI, 95% confidence interval
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The main existing treatment options:
Through 28 February 30 September 2021, other COVID -19 vaccines were authorized and
recommended for use in the United States including vaccines from Moderna
(NCT04470427), and Johnson & Johnson /Janssen (NCT04505722) . Others may
subsequently be approved.
Natural history of the indicated con dition in the untreated population, including
mortality and morbidity:
Symptoms of COVID -19
The clinical manifestations of COVID -19 vary widely, from asymptomatic infection in
17-20%,67,45% across age groups , 68, 69 70, 71 to critical illness and death. The rate of
asymptomatic infection decreases with increasing age and long -term care facilities are
associated with a lower rate of asymptomatic infection when compared to household
transmission or other healthcare facilities .71 A recent meta -analysis has estimated that 46.7%
of infections in children are asymptomatic.71 The most common symptoms of COVID -19 are
fever, cough, and shortness of breath (Table 39).72 for both children and adults ( Table 47).73,
74 .
Table 47. Signs and symptoms among 291 pediatric (age <18 years) and 10,944 adult
(age 18 –64 years) patientsa with laboratory confirmed COVID -19 —
United States, 12 February – 2April 202046 73
No. (%) with sign/symptom
Sign/Symptom Pediatric Adult
Fever, cough, or shortness of breathb 213 (73) 10,167 (93)
Feverd 163 (56) 7,794 (71)
Cough 158 (54) 8,775 (80)
Shortness of breath 39 (13) 4,674 (43)
Myalgia 66 (23) 6,713 (61)
Runny nosec 21 (7.2) 757 (6 9)
Sore throat 71 (24) 3,795 (35)
Headache 81 (28) 6,335 (58)
Nausea/Vomiting 31 (11) 1,746 (16)
Abdom inal paindpainc 17 (5.8) 1,329 (12)
Diarrhea 37 (13) 3,353 (31)
a. Cases were included in the denominator if they had a known symptom status for fever, cough, s hortness
of breath, nausea/vomiting, and diarrhea. Total number of patients by age group: <18 years (N = 2,572), 18 –
64 years (N = 113,985).
b. Includes all cases with one or more of these symptoms.
c. Runny nose and abdominal pain were less frequently completed than other symptoms; therefore,
percentages with these symptoms are likely underestimates.
d. Patients were included if they had information for eith er measured or subjective fever variables and were co nsidered
to have a fever if “yes” was indicated for either variable
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Progression and Timeline of Mild to Moderate Disease
Mild to moderate disease is defined as the absence of viral pneumonia and hypoxia. For those
who develop symptoms, the incubation pe riod is usually 4 to 5 days, with 97.5%
experiencing symptoms within 11 days of exposure.75,76 Those with mild COVID -19 recover
at home with supportive care and guidance to self -isolate. Those with moderate disease are
monitored at home and are sometimes recommended to be hospitalized if conditions
worsen .48. 76 Data on rates of re -infection are limited but variants that are not neutralized by
immune antisera, such as the recent beta ( South African ) variant, may lead to increased risk
of re -infectio n in the future .47. 75
Progression and Timeline of Severe Disease Requiring Hospitalization
Those with severe disease will require hospitalization to manage their illness. Based on data
that have been systematically collected for the US by the CDC between 01 August 2020 and
02 March 05 September 2021, there were 1,814,606 2,816,280 new hospital admissions for
patients with confirmed COVID -19 in the US.77 For the week ending 28 February 22 August
2021, 103.5 patients per 100,000 population were hospitalized hospitalised due to COVID -19
in 2221 countries of the EU/EEA with available data .78 Based on data from 23 states and
New York City, as of August 19, 2021, 1.6% -3.6% of children with COVID -19 have been
hospi talised and 0.0 -0.03% of children with COVID -19 have died.79
The most common symptoms in patients are fever (42-80%), shortness of breath (35 -71%),
fatigue (33 -62%), cough (77 -84%), chills (63%), myalgias (63%), headache (59%), and
diarrhea (33%) .80,81,82,83 COVID -19 patients also commonly experience gustatory disorders
(44%) and olfactory disorders (53%).84 Among unhospitalised children < 18 years of age,
89% experienced one or more typical symptoms of COVID, including fever, cough,
shortness of breath , and 22% experienced all three. 81Approximately 17% to 40% of those
hospitalized hospitalised with COVID -19 experience severe symptoms necessitating intensive
care.23,24,28,51 29,80 with 31% of children hospitalised experiencing severe COVID -19 that
necessitates intensive care or invasive ventilation or ends in death. Risk factors for severe
COVID -19 in hospitalised child ren include presence of a comorbid condition, younger age,
and male sex .38 More than 75% of patients hospitalized hospitali sed with COVID -19 require
supplemental - oxygen.85
Studies early in the pandemic demonstrated that time from onset of illness to ARDS was
8--12 -days and time from onset of illness to ICU admission was 9.5 –12 days .47. 75 In 17
countries of the EU/EEA with available data, 1.8 patients per 100,000 population were in the
ICU due to COVID -19 for the week ending 28 February 2021 .50.86 A recent meta -analysis
found that, of patients <19 years of age, 11% went to the ICU, non -invasive ventilation was
administered among 12%, and 4% required mechanical ventilation .45. 69
Mortality
As of 07 March 17 August 2021 , there were 522,973 620,493 deaths reported in the US for all
age groups among 28,771,749 36,951,181 cases ( 1.87% of cases ).49).87 As of 28 February 17
August 2021 there wer e 547,267 746,566 deaths reported for all age groups in the EU/EEA
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among 22,527,370 35,381,520 cases ( 2.41% of cases).88 As of 7 March 17 August 2021, the
UK has seen 124,736 131,466 deaths from COVID -19 in all age groups among
4,231,166 6,352,224 cases ( 2.91% of cases) .89 According to a recent meta -analysis of
pediatric paediatric studies published through October 2020, the mortality for paediatric
patients <19is 0.1 -2%.69, 23 In a study from January through June 2020 using the National
Child Mortality Database (NCMD) in England, 5.7% of 437 children 0 -17 years of age is
2%.45who died were SARS -CoV -2 PCR -positive and those who died of COVID -19 were
older and were more likely to be non -White ethnicity .90
Mortality data are also presented from Worldometer, an independ ent
organization organi sation that publishes current, reliable COVID -19 statistics online.1714 The
mortality of SARS -CoV -2 infection is defined as the cumulative number of deaths among
detected cases.
As of 03 March 15 August 2021, the overall SARS -CoV -2 mortality for the EU + UK was
677,146 878,344 deaths, or 132171 per 100,000 people. Reported mortality among EU
countries and the UK ranged from 1418 to 195312 deaths per 100,000 ( Table 35).Table 40).
Finland and Cyprus reported the lowest mortality; Hungary, Czech Republic, Belgium and
Slove niaBulgaria reported the highest.1515
In the US, as of 03 March 15 August 2021, the mortality was 531,652 637,439 deaths (160191
per 100,000 people). Mortality in the US was very similar to that of EU countries Hungary,
Portugal, and Italy. the UK (192 per 100,000) . 15 15
Overall reported mortality among hospitalized hospitali sed COVID -19 patients varies from
12.8% to 26% in the EU and UK. 28, UK, and US .29,30,91,92 31, 93,94. Mortality rates are
declining over time, presumably due to an improved understanding of COVID -19 and its
management .58,95.96
Complications of COVID -19 and Long -COVID
Complications of COVID -19 include impaired function of the heart, brain, lung, liver,
kidney, and coagulation system .23,25,54. 24,27, 97 Based on a meta -analysis of 42 studies, the
risk of thromboembolism was 21% overall and 31% in the ICU, with the pooled odds of
mortality being 74% higher among those who experienced thromboembolism compared to
those who did not.98
COVID -19 symptoms can persist weeks or months beyond the acute infection.99,100 The
NICE guideline scope published on 30 October 2020 defined “Long COVID” signs and
symptoms that continue or develop after acute COVID‑19. It includes both ongoing
symptomatic COVID‑19 (from 4 to 12 weeks) and post‑COVID‑19 syndrome (12 weeks or
more and for which signs and symptoms are not explained by an alternative diagnosis).101
A meta analysis of 31 studies among patients between 18 to 49 years of age found that
COVID -19 symptoms were experien ced for 14 days to 3 months post -infection, including
persistent fatigue (39 –73%), breathlessness (39 –74%), decrease in quality of life (44 –69%),
impaired pulmonary function, abnormal CT findings including pulmonary fibrosis (39 –83%),
evidence of peri -/perimyo -/myocarditis (3 –26%), changes in microstructural and functional
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brain integrity with persistent neurological symptoms (55%), increased incidence of
psychiatric diagnoses (5.8% versus 2.5 –3.4% in controls), and incomplete recovery of
olfactory and gust atory dysfunction (33 –36%).102 Post-acute COVID symptoms in children
with asymptomatic or mild disease appear to be less severe than in adults, with the most
common symptoms being a post -viral cough (4%), fatigue (2%), or both symptoms (1%)
with the durati on of symptoms lasting 3 to 8 weeks.103
Children who are infected with COVID -19 are at risk of subsequent multisystem
inflammatory syndrome (MIS -C) and often develop a rash following resolution of COVID -
19.104,105,45.69,106,107 As of August 19, 2021 there were 4,403 cases of MIS -C reported to
health departments in the U S. 108 Additional symptoms of MIS -C include abdominal pain,
bloodshot eyes, chest tightness or pain, diarrhea, lethargy, headache, low blood pressure,
neck pain, and vomiting.109
Important co -morbid ities:
Important comorbidities in hospitalized COVID -19 patients include hypertension, diabetes,
obesity, cardiovascular disease, chronic pulmonary disease or asthma, chronic kidney
disease, cancer, and chronic liver disease .24,25,26,51,54. 25, 26, 27, 80, 83 Prevalence of these
conditions have been reported to be lower in mild cases and higher among fatal cases, as
shown as shown for European EU/EEA countries in Table 40Table 48 below . using TESSy
data posted on 12 Aug ust 2021 .110
Table 48. Preconditions among COVID -19 Patients in EU/EEA and UK , by Severity
of Disease. Case -based Data from TESSy Produced 04 March Reported 12
August 2021110
EU/EEA, produced report ed on 04 March 12 August 2021
Mild Hosp Hosp italised Severe Fatal
Total N 1,155,969 948,252 214,784 356,472 35,468 52,365 67,011 109,878
Asplenia (%) 0 0 0 0
Asthma (%) 056 1.62 1.73 1.62
Cancer, malignancy (%) 23.1 7.29.1 9.710 9.311.1
Cardiac disorder, excluding
hypertension (%) 6.29.1 18.423.7 20.722.8 24.729.4
Chronic lung disease, excluding
asthma (%) 1.8 4.73.6 5 34.4 5.3.6
Current smoking (%) 0.9 0.31 0.42 0.1
Diabetes (%) 3 35 13.917.1 18 920.5 15.619.2
Haematolo
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