A Randomized, Placebo-controlled Crossover Study to Assess the Safety of Administering a Second Dose of a COVID-19 mRNA Vaccine in Individuals Who Experienced a Systemic Allergic Reaction to an Initial Dose
Phase: PHASE2
Conditions: Systemic Allergic Reaction
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Abbreviated Title: COVAAR
1
Version Date: 19 October 2022
Abbreviated Title: COVID vaccine allergy reaction (COVAAR)
NIH IRB #: 000460
Version Date: 19 October 2022
Title: A randomized, placebo-controlled crossover study to assess the safety of administering a 
second dose of a COVID-19 mRNA vaccine in individuals who experienced a systemic allergic 
reaction to an initial dose
National Institutes of Health 
(NIH) Principal Investigator:
Pamela A. Guerrerio, M.D., Ph.D.
Laboratory of Allergic Diseases (LAD)
National Institute of Allergy and Infectious Diseases (NIAID)
Building 10, Rm 11N240B
10 Clinical Center Drive
Bethesda, MD 20892
Phone: 301-402-9782
E-mail: pamela.guerrerio@nih.gov
Investigational Agents:
Drug Name:
Comirnaty (COVID-19 Vaccine, mRNA); Pfizer-BioNTech COVID-
19 Vaccine, Bivalent (Original and Omicron BA.4/BA.5).
Investigational New Drug 
(IND) Number:
27537
IND Sponsor:
Office of Clinical Research Policy and Regulatory Operations 
(OCRPRO), Division of Clinical Research (DCR), NIAID, NIH
Manufacturer:
Pfizer-BioNTech

Abbreviated Title: COVAAR
2
Version Date: 19 October 2022
TABLE OF CONTENTS 
LIST OF TABLES...........................................................................................................................5
STATEMENT OF COMPLIANCE ................................................................................................6
1
PROTOCOL SUMMARY.......................................................................................................7
1.1
Synopsis ............................................................................................................................7
1.2
Schema............................................................................................................................12
1.3
Schedule of Activities (SOA) .........................................................................................13
2
INTRODUCTION .................................................................................................................18
2.1
Study Rationale...............................................................................................................18
2.2
Background .....................................................................................................................18
2.3
Risk/Benefit Assessment.................................................................................................23
2.3.1
Known Potential Risks ............................................................................................23
2.3.2
Known Potential Benefits........................................................................................25
2.3.3
Assessment of Potential Risks and Benefits............................................................25
3
OBJECTIVES AND ENDPOINTS.......................................................................................26
4
STUDY DESIGN ..................................................................................................................30
4.1
Overall Design ................................................................................................................30
4.2
Scientific Rationale for Study Design.............................................................................33
4.3
Justification for Dose ......................................................................................................33
5
STUDY POPULATION........................................................................................................33
5.1
Inclusion Criteria.............................................................................................................33
5.2
Exclusion Criteria ...........................................................................................................34
5.2.1
Exclusion of Special Populations ............................................................................34
5.3
Inclusion of Vulnerable Participants...............................................................................35
5.3.1
Participation of Children..........................................................................................35
5.3.2
Adult Subjects Who Lack Capacity to Consent to Research Participation .............35
5.3.3
Participation of NIH Staff or Family Members of Study Team Members..............35
5.4
Inclusion of Pregnant Women, fetuses or neonates ........................................................35
5.5
Lifestyle Considerations .................................................................................................35
5.6
Screen Failures................................................................................................................35
5.7
Strategies for Recruitment and Retention .......................................................................36
5.7.1
Costs ........................................................................................................................36

Abbreviated Title: COVAAR
3
Version Date: 19 October 2022
5.7.2
Compensation ..........................................................................................................36
6
STUDY INTERVENTIONS .................................................................................................37
6.1
Study Interventions Administration................................................................................37
6.1.1
Study Intervention Description................................................................................37
6.1.2
Dosing and Administration......................................................................................37
6.1.3
Booster Vaccination.................................................................................................37
6.2
Preparation/Handling/Storage/Accountability................................................................38
6.2.1
Acquisition and Accountability ...............................................................................38
6.2.2
Formulation, Appearance, Packaging, and Labeling...............................................38
6.2.3
Product Storage and Stability ..................................................................................38
6.2.4
Preparation...............................................................................................................38
6.3
Measures to Minimize Bias: Randomization and Blinding ............................................39
6.4
Study Intervention Compliance ......................................................................................40
6.5
Concomitant Therapy......................................................................................................40
7
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .....................................................................................41
7.1
Discontinuation of Study Intervention............................................................................41
7.2
Participant Discontinuation/Withdrawal from the Study................................................41
7.3
Lost to Follow-up............................................................................................................41
8
STUDY ASSESSMENTS AND PROCEDURES.................................................................41
8.1
Screening Procedures......................................................................................................41
8.1.1
Screening Activities Performed Prior to Obtaining Informed Consent...................41
8.1.2
Screening Activities Performed After a Consent for Screening Has Been Signed .42
8.2
Efficacy Assessments......................................................................................................42
8.2.1
Clinical Evaluations.................................................................................................42
8.2.2
Biospecimen Evaluations.........................................................................................45
8.2.3
Samples for Genetic/Genomic Analysis..................................................................47
8.3
Safety and Other Assessments ........................................................................................48
8.4
Safety Definitions, Management, and Reporting............................................................49
8.4.1
Definitions ...............................................................................................................49
8.4.2
Documenting, Assessing, Recording, and Reporting Events ..................................53
8.4.3
Withdrawal Criteria for an Individual Subject ........................................................58
8.4.4
Additional Safety Oversight ....................................................................................59

Abbreviated Title: COVAAR
4
Version Date: 19 October 2022
8.4.5
Pausing Rules...........................................................................................................60
8.4.6
Halting Rules for the Protocol .................................................................................60
8.5
Unanticipated Problems. .................................................................................................61
8.5.1
Definition of Unanticipated Problems.....................................................................61
8.5.2
Unanticipated Problem Reporting ...........................................................................61
8.5.3
NIH Intramural IRB Reporting of IND Safety Reports...........................................61
9
STATISTICAL CONSIDERATIONS ..................................................................................61
9.1
Statistical Hypothesis......................................................................................................62
9.2
Sample Size Determination.............................................................................................62
9.3
Populations for Analyses ................................................................................................64
9.3.1
Evaluable for Toxicity .............................................................................................64
9.3.2
Evaluable Non-Target Disease Response................................................................64
9.4
Statistical Analyses .........................................................................................................64
9.4.1
General Approach....................................................................................................64
9.4.2
Analysis of the Primary Endpoints..........................................................................65
9.4.3
Analysis of the Secondary Endpoint(s) ...................................................................65
9.4.4
Safety Analyses .......................................................................................................65
9.4.5
Baseline Descriptive Statistics.................................................................................66
9.4.6
Planned Interim Analyses........................................................................................66
9.4.7
Sub-Group Analyses................................................................................................66
9.4.8
Tabulation of individual Participant Data................................................................66
9.4.9
Exploratory Analyses...............................................................................................66
10
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................67
10.1
Informed Consent Process...........................................................................................67
10.1.1
Consent/Assent Procedures and Documentation.....................................................67
10.1.2
Consent for Minors When They Reach the Age of Majority ..................................68
10.1.3
Considerations for Consent of NIH Staff, or Family Members of Study Team 
Members ................................................................................................................................69
10.2
Study Discontinuation and Closure.............................................................................69
10.3
Confidentiality and Privacy.........................................................................................70
10.4
Future Use of Stored Specimens and Data..................................................................70
10.5
Safety Oversight..........................................................................................................70
10.6
Clinical Monitoring .....................................................................................................71

Abbreviated Title: COVAAR
5
Version Date: 19 October 2022
10.7
Quality Assurance and Quality Control ......................................................................71
10.8
Data Handling and Record Keeping............................................................................71
10.8.1
Data Collection and Management Responsibilities.................................................71
10.8.2
Study Records Retention .........................................................................................72
10.9
Protocol Deviations and Non-Compliance..................................................................72
10.9.1
NIH Definition of Protocol Deviation .....................................................................72
10.10
Reporting to the NIAID Clinical Director...................................................................72
10.11
Publication and Data Sharing Policy...........................................................................72
10.11.1 Human Data Sharing Plan .......................................................................................72
10.11.2 Genomic Data Sharing Compliance ........................................................................73
10.12
Conflict of Interest Policy ...........................................................................................73
11
ABBREVIATIONS ...............................................................................................................74
12
REFERENCES ......................................................................................................................76
Appendix A. Modified CoFAR Grading Scale for Systemic Allergic Reactions Version 3.0......79
Appendix B. Brighton Collaboration Criteria ...............................................................................80
LIST OF TABLES
Table 1: Composition of Pfizer-BioNTech COVID-19 Vaccine and Moderna COVID-19 
Vaccine ..........................................................................................................................................22
Table 2: Standard Times for Follow-up of Events ........................................................................53
Table 3: PSEE List and Reporting.................................................................................................53
Table 4: ESI List and Reporting ....................................................................................................53
Table 5: Exact 95% Clopper Pearson Confidence Intervals for Primary Outcome, by Sample Size 
and Proportion with Systemic Allergic Reaction to Second Dose ................................................63
Table 6: Exact 95% Confidence Intervals for the Difference in Reaction Rate Between Vaccine 
and Placebo Arms on Day 1 ..........................................................................................................63
Table 7: Exact 95% Confidence Intervals for the Risk Difference Comparing each Individual’s 
Vaccine Phase to Placebo Phase Response Using McNemar’s Approach....................................64

Abbreviated Title: COVAAR
6
Version Date: 19 October 2022
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
NIH-funded investigators and clinical trial site staff who are responsible for the conduct, 
management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent using a previously approved consent form.

Abbreviated Title: COVAAR
7
Version Date: 19 October 2022
1
PROTOCOL SUMMARY
1.1
SYNOPSIS
Title:
A randomized, placebo-controlled crossover study to assess the safety of 
administering a second dose of an mRNA-based COVID-19 vaccine in 
individuals who experienced a systemic allergic reaction to an initial dose
Study Description:
This is a single-site study to determine the safety of administering a dose of 
the Pfizer-BioNTech mRNA coronavirus disease 2019 (COVID-19) 
vaccine (Comirnaty) to individuals who experienced a systemic allergic 
reaction to their first full dose of the same vaccine or the Moderna mRNA 
vaccine, and to investigate possible mechanisms underlying allergic 
reactions. 
Objectives:
Primary Objective:  
1.
Assess the proportion of participants who develop a systemic 
allergic reaction (Consortium for Food Allergy Research [CoFAR; 
see Appendix A] grade 2 reaction and above regardless of tryptase, 
or CoFAR grade 1 with elevated tryptase [1.2 X baseline plus 
2ng/mL]) to the Pfizer-BioNTech COVID-19 vaccine after 
previously demonstrating a systemic allergic reaction (CoFAR 
Grade 2 or 3 reaction regardless of tryptase OR Grade 1 reaction 
with elevated tryptase [1.2 X baseline plus 2ng/mL]) to their first 
full dose of the same vaccine or the Moderna COVID-19 vaccine. 
Secondary Objectives: 
1.
Assess the proportion of participants who develop a severe 
systemic allergic reaction (CoFAR Grade 3 reaction or higher 
regardless of tryptase) to the Pfizer-BioNTech COVID-19 vaccine 
after previously demonstrating a systemic allergic reaction (CoFAR 
Grade 2 or 3 reaction regardless of tryptase OR Grade 1 reaction 
with elevated tryptase [1.2 X baseline plus 2ng/mL]) to their first 
full dose of the same vaccine or the Moderna COVID-19 vaccine.
2.
Assess the proportion of participants who develop a mild-
moderate allergic reaction (CoFAR Grade 1 or 2 reaction 
regardless of tryptase) to the Pfizer-BioNTech COVID-19 vaccine 
after previously demonstrating a systemic allergic reaction (CoFAR 
Grade 2 or 3 reaction regardless of tryptase OR Grade 1 reaction 
with elevated tryptase [1.2 X baseline plus 2ng/mL]) to their first 
full dose of the same vaccine or the Moderna COVID-19 vaccine.
3.
Assess the proportion of participants with anaphylactic reactions 
(Levels 1-3) per Brighton Collaboration Criteria (see Appendix B) 
to the Pfizer-BioNTech COVID-19 vaccine after previously 
demonstrating a systemic allergic reaction (CoFAR Grade 2 or 3 
reaction OR Grade 1 reaction with elevated tryptase [1.2 X baseline 
plus 2ng/mL]) to their first full dose of the same vaccine or the 
Moderna COVID-19 vaccine.
4.
Assess the proportion of participants who develop a systemic 
allergic reaction (CoFAR Grade 2 reaction or higher regardless of 
tryptase OR Grade 1 reaction with elevated tryptase [1.2 X baseline 

Abbreviated Title: COVAAR
8
Version Date: 19 October 2022
plus 2ng/mL]) to the Pfizer-BioNTech COVID-19 vaccine after 
previously demonstrating a systemic allergic reaction (CoFAR 
Grade 2 or 3 reaction regardless of tryptase OR Grade 1 reaction 
with elevated tryptase [1.2 X baseline plus 2ng/mL]) to their first 
full dose of the same vaccine or the Moderna COVID-19 vaccine 
compared to the rate of these reactions following placebo 
administration.
5.
Compare the severity of allergic reactions to the first dose of the 
Pfizer-BioNTech or Moderna COVID-19 vaccine to the severity of 
the reaction following administration of a subsequent dose of the 
Pfizer-BioNTech vaccine in individuals who experienced a 
systemic allergic reaction (CoFAR grade 2 reaction and above 
regardless of tryptase, or CoFAR grade 1 with elevated tryptase 
[1.2 X baseline plus 2ng/mL]) to their first full dose of the Pfizer-
BioNTech or Moderna COVID-19 vaccine.
Exploratory Objectives:
1.
Assess the risk of having a systemic allergic reaction to a dose of 
the Pfizer-BioNTech COVID-19 vaccine in participants who 
previously demonstrated a systemic allergic reaction (CoFAR 
Grade 2 or 3 reaction regardless of tryptase OR Grade 1 reaction 
with elevated tryptase [1.2 X baseline plus 2ng/mL]) to their first 
full dose of the same vaccine or the Moderna COVID-19 according 
to baseline covariates. 
2.
Examine possible mechanisms of allergic reactions to mRNA-
based COVID-19 vaccines.
3.
Assess innate and adaptive immune responses, including functional 
antibody levels, to the Pfizer-BioNTech COVID-19 vaccine.
4.
Investigate mental health characteristics of participants who 
experience an allergic reaction to the COVID-19 vaccine.
5.
Assess psychological impact of allergic reactions to the COVID-19 
vaccine and examine changes in stress levels over time.
6.
Assess anxiety levels in participants and examine changes in 
anxiety over time. 
7.
Assess the proportion of participants who experience no reaction or 
only a mild reaction (CoFAR Grade 2 or below) to a booster dose 
of the Pfizer-BioNTech vaccine after previously demonstrating a 
systemic allergic reaction (CoFAR Grade 2 or 3 reaction regardless 
of tryptase OR Grade 1 reaction with elevated tryptase [1.2 X 
baseline plus 2 ng/mL]) to their first full dose of the Pfizer-
BioNTech or Moderna COVID-19 vaccine and no allergic reaction 
or a mild reaction (CoFAR Grade 2 or below) to a subsequent 
(second) dose of the Pfizer-BioNTech vaccine.
8.
Assess the development of autoantibodies after COVID-19 
vaccination.
  

Abbreviated Title: COVAAR
9
Version Date: 19 October 2022
Endpoints:
Primary Endpoint:
1.
The proportion of participants who previously demonstrated a 
systemic allergic reaction (CoFAR Grade 2 or 3 reaction regardless 
of tryptase OR Grade 1 reaction with elevated tryptase [1.2 X 
baseline plus 2ng/mL]) to their first full dose of the Pfizer-
BioNTech or Moderna COVID-19 vaccine who experience a 
systemic allergic reaction (CoFAR Grade 2 and above reaction 
regardless of tryptase, or CoFAR grade 1 with elevated tryptase 
[1.2 X baseline plus 2ng/mL]) within the 3-hour post-vaccine 
observation period to a subsequent dose of the Pfizer-BioNTech 
vaccine.
Secondary Endpoints: 
2.
The proportion of participants who previously demonstrated a 
systemic allergic reaction (CoFAR Grade 2 or 3 reaction regardless 
of tryptase OR Grade 1 reaction with elevated tryptase [1.2 X 
baseline plus 2ng/mL]) to their first full dose of the Pfizer-
BioNTech or Moderna COVID-19 vaccine who experience a 
severe systemic allergic reaction (CoFAR grade 3 reaction and 
above) within the 3-hour post-vaccine observation period to a 
subsequent dose of the Pfizer-BioNTech vaccine.
3.
The proportion of participants who previously demonstrated a 
systemic allergic reaction (CoFAR Grade 2 or 3 reaction regardless 
of tryptase OR Grade 1 reaction with elevated tryptase [1.2 X 
baseline plus 2ng/mL]) to their first full dose of the Pfizer-
BioNTech or Moderna COVID-19 vaccine who experience a mild-
moderate allergic reaction (CoFAR grade 1 or 2 reaction 
regardless of tryptase) within the 3-hour post-vaccine observation 
period to a subsequent dose of the Pfizer-BioNTech vaccine.
4.
The proportion of participants who previously demonstrated a 
systemic allergic reaction (CoFAR Grade 2 or 3 reaction regardless 
of tryptase OR Grade 1 reaction with elevated tryptase [1.2 X 
baseline plus 2ng/mL]) to their first full dose of the Pfizer-
BioNTech or Moderna COVID-19 vaccine who experience an 
anaphylactic reaction (Levels 1-3) per Brighton Collaboration 
Criteria within the 3-hour post-vaccine observation period to a 
subsequent dose of the Pfizer-BioNTech vaccine. 
5.
The proportion of participants who previously demonstrated a 
systemic allergic reaction (CoFAR Grade 2 or 3 reaction regardless 
of tryptase OR Grade 1 reaction with elevated tryptase [1.2 X 
baseline plus 2ng/mL]) to their first full dose of the Pfizer-
BioNTech or Moderna COVID-19 vaccine who experience a 
systemic allergic reaction (CoFAR grade 2 reaction and above 
regardless of tryptase, or CoFAR grade 1 with elevated tryptase 
[1.2 X baseline plus 2ng/mL]) within the 3-hour post-vaccine 
observation period to a subsequent dose of the Pfizer-BioNTech 
vaccine compared to the rate of these reactions following placebo 
administration.

Abbreviated Title: COVAAR
10
Version Date: 19 October 2022
6.
The proportion of participants who previously demonstrated a 
systemic allergic reaction (CoFAR Grade 2 or 3 reaction regardless 
of tryptase OR Grade 1 reaction with elevated tryptase [1.2 X 
baseline plus 2ng/mL]) to their first full dose of the Pfizer-
BioNTech or Moderna COVID-19 vaccine who develop a lower or 
higher grade allergic reaction within the 3-hour post-vaccine 
observation period to a subsequent dose of the Pfizer-BioNTech 
vaccine.
Exploratory Endpoints:
7.
Prevalence of polyethylene glycol (PEG) and severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in 
each participant at baseline.
8.
Changes in anti-PEG and SARS-CoV-2 antibodies in each 
participant approximately 1 and 5 months after receiving the dose 
of the Pfizer-BioNTech vaccine administered on study.
9.
Prevalence of positive skin testing to the vaccine and/or vaccine  
components including PEG- and polysorbate 80-containing 
medications. 
10. Changes in biomarkers from baseline to post-dose of the Pfizer-
BioNTech vaccine administered on study (e.g., known mediators of 
systemic reactions due to mast cell activation, markers of 
inflammatory response, markers of basophil and neutrophil 
activation, markers associated with activation of the classical and 
alternative complement pathways or kinin system, proteomics, 
metabolomics).
11. Changes in blood transcriptomics after vaccination.
12. Changes in innate and adaptive immune responses including 
functional antibody levels after vaccination.
13. Mental health/anxiety questionnaire scores and anxiety level 
ratings at baseline.
14. Results of psychiatric consultation/mental health interview.
15. Changes in mental health/anxiety questionnaire scores and anxiety 
level ratings over the study period.
16. The proportion of participants who previously demonstrated a 
systemic allergic reaction (CoFAR Grade 2 or 3 reaction regardless 
of tryptase OR Grade 1 reaction with elevated tryptase [1.2 X 
baseline plus 2 ng/mL]) to their first full dose of the Pfizer-
BioNTech or Moderna COVID-19 vaccine and no allergic reaction 
or a mild reaction (CoFAR Grade 2 or below) to a subsequent 
(second) dose of the Pfizer-BioNTech vaccine who experience no 
reaction or only a mild reaction (CoFAR Grade 2 or below) to a 
booster dose of the Pfizer-BioNTech vaccine administered 
approximately 5 months after the second dose.
17. The development of autoantibodies post-second and post-booster 
doses of the COVID-19 mRNA vaccines.

Abbreviated Title: COVAAR
11
Version Date: 19 October 2022
Study Population:
Up to 100 male and female participants ages 16-69 years of age who 
experienced a systemic allergic reaction (CoFAR Grade 2 or 3 reaction 
regardless of tryptase OR Grade 1 reaction with elevated tryptase [1.2 X 
baseline plus 2 ng/mL]) after receiving their first dose of the Pfizer-
BioNTech or Moderna COVID-19 vaccine.
Phase:
N/A
Description of 
Sites/Facilities 
Enrolling Participants:  
This is a single site study; all participants will be enrolled at the NIH 
Clinical Center. 
Description of Study 
Intervention:
Participants who experienced a systemic allergic reaction after receiving 
their first full dose of the Pfizer-BioNTech or Moderna COVID-19 vaccine 
will be enrolled and receive a subsequent dose of the Pfizer-BioNTech 
vaccine and placebo in a randomized order on consecutive days.
Study Duration:
6 years
Participant Duration:
Approximately 5 or 6 months

Abbreviated Title: COVAAR
12
Version Date: 19 October 2022
1.2
SCHEMA
Prior to 
Enrollment
Visit 1
Days 0-3
Visit 2
Day 7 (±2)
Visit 3
Day 30 (-3/+7)
Visit 4
Month 5 
(+/-2 weeks)
Visit 5 (for 
booster dose
recipients only)
Up to 7 days
after Visit 4
Visit 6 (for
booster dose
recipients only)
Month 6
(-3/+14 days)
Recruitment & Screening: 
- Screen potential participants by phone.
- In-person screening at NIH only for individuals with certain chronic/comorbid 
conditions.
- Screening procedures must be completed within 30 days prior to Day 1.
- Informed consent may be performed up to 60 days prior to or at Visit 1 (depending on 
screening requirements for individuals [phone or in-person]).
 Perform post-vaccination assessments (refer to Section 1.3, Schedule of Activities)
Follow-up assessments of study endpoints and safety (refer to Section 1.3, Schedule of 
Activities)
- Perform baseline assessments (refer to 
Section 1.3, Schedule of Activities)
- Randomize to study vaccine order
- Administer study vaccines
Placebo 
vaccine
Active 
vaccine
Phone follow-up (refer to Section 1.3, Schedule of Activities)
Crossover
Enrollment and 
Randomization:
Follow-up assessments of study endpoints and safety (refer to Section 1.3, Schedule of 
Activities), and booster vaccination (as applicable). Final visit for participants who do not 
receive a booster vaccination.
Phone follow-up (refer to Section 1.3, Schedule of Activities). 
Follow-up assessments of study endpoints and safety (refer to Section 1.3, Schedule of 
Activities). Final visit for participants who receive a booster vaccination.

Abbreviated Title: COVAAR
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Version Date: 19 October 2022
1.3
SCHEDULE OF ACTIVITIES (SOA)
Visit (location c)
Screening a 
(remote/NIH)
Visit 1 (NIH/
inpatient)
Visit 2 (remote)
Visit 3 (NIH)
Visit 4 (NIH)
Visit 5 (Booster 
recipients only)
(remote)
Visit 6 (Booster 
recipients only) 
(NIH)
Unscheduled 
visits b (remote/
NIH)
Timepoint (window)
Day -30-0
Enrollment/Day 0 d
Day 1
Day 2
Day 3 e
Day 7 (±2)
Day 30 (-3/+7)
Month 5 (±2 weeks)
Up to 7 days after 
Visit 4 (single 
timepoint unless 
additional safety 
follow-up needed) 
Month 6 (-3/+14 days)
Procedures
Informed consent
X f
(X) f
Consent addendum x
X
Demographics
X
Medical history
X
X
X
X
X
X
X
X
X
X
X
Additional screening procedures 
(per-participant basis) g
(X)
Assessment of adverse events h
X
X
X
X
X
X
X
X
X
X
Randomization
X
IV line insertions (1 or 2 sites)
X
X i
Administer study vaccine h
X
X

Abbreviated Title: COVAAR
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Version Date: 19 October 2022
Visit (location c)
Screening a 
(remote/NIH)
Visit 1 (NIH/
inpatient)
Visit 2 (remote)
Visit 3 (NIH)
Visit 4 (NIH)
Visit 5 (Booster 
recipients only)
(remote)
Visit 6 (Booster 
recipients only) 
(NIH)
Unscheduled 
visits b (remote/
NIH)
Timepoint (window)
Day -30-0
Enrollment/Day 0 d
Day 1
Day 2
Day 3 e
Day 7 (±2)
Day 30 (-3/+7)
Month 5 (±2 weeks)
Up to 7 days after 
Visit 4 (single 
timepoint unless 
additional safety 
follow-up needed) 
Month 6 (-3/+14 days)
Administer Pfizer-BioNTech 
vaccine booster (optional) j
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
X
X
Targeted physical exam
(X)
X
X
X
X
X
X
X
(X)
Height and weight
X
Vital signs k
(X)
X
X
X
X
X
X
X
Peak flow measurement l
X
X
X
X
X
X
Impulse oscillometry l
X
X
X
X
X
X
Nasal swab m
X
Serum pregnancy test n
X
X
Mental health/anxiety 
questionnaires o, p
X
X
X
Patient Health Questionnaire-9 p
X
X q
X q

Abbreviated Title: COVAAR
15
Version Date: 19 October 2022
Visit (location c)
Screening a 
(remote/NIH)
Visit 1 (NIH/
inpatient)
Visit 2 (remote)
Visit 3 (NIH)
Visit 4 (NIH)
Visit 5 (Booster 
recipients only)
(remote)
Visit 6 (Booster 
recipients only) 
(NIH)
Unscheduled 
visits b (remote/
NIH)
Timepoint (window)
Day -30-0
Enrollment/Day 0 d
Day 1
Day 2
Day 3 e
Day 7 (±2)
Day 30 (-3/+7)
Month 5 (±2 weeks)
Up to 7 days after 
Visit 4 (single 
timepoint unless 
additional safety 
follow-up needed) 
Month 6 (-3/+14 days)
Anxiety rating scale
X
X
X r
X r
X
X
X
X
X
X
Psychiatric consultation s
X
Mental health interview benefit 
and burden questionnaire
X
Urine collection t
X
X
X
Blood collection u
(X)
X
X
X
X
X
X
(X)
Skin allergy testing
X v
Clinical photography w
X
X
X
X
X
X
(X)
(X) = Only performed at the NIH/not included in a remote assessment.
Abbreviations: NIH, National Institutes of Health; IV, intravenous.
a All individuals will initially be screened remotely by phone/email/videoconference. If an individual has a co-morbid condition(s) that may 
increase their risk of having a severe allergic reaction, they may be asked to come to the NIH Clinical Center for additional studies, such as 
pulmonary function testing, echocardiogram, or blood laboratory testing, that are felt to be clinically necessary (based on the discretion of the 
study team) to ensure that they are medically stable to undergo the study intervention. These additional screening procedures may be performed on 
day 0 if logistically feasible.

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b If a participant develops symptoms of a reaction post-visit or other concerns arise related to the vaccine administration, the participant will be 
instructed to contact study personnel and may be asked to return to the NIH for an unscheduled visit. If the participant presents with symptoms for 
a suspected allergic reaction, the investigator may elect to collect blood samples, at their discretion, for the assessment of serum biomarkers, 
complement activation, and other research studies. If the participant is not able to return to the NIH, they may be directed to receive medical care 
locally. Clinical care labs and research labs may be obtained.
c Some procedures/visits may be performed remotely via phone/email/videoconference.
d Depending on logistics and scheduling, some procedures indicated for Day 0 may be performed prior to study vaccination on Day 1 (e.g., IV 
insertion, pregnancy test). Subjects will be enrolled after eligibility is confirmed on Day 0.
e Participants will be discharged on day 3, unless they require additional treatment due to a reaction. The IV line(s) will be removed once 
participant is stable and before discharge.
f Informed consent may be obtained up to 60 days prior to Day 1. For individuals who can complete screening procedures remotely (i.e., those without 
comorbid conditions that would require additional in-person assessments), informed consent may be obtained remotely during screening or in person 
at Visit 1 prior to any study procedures. Individuals with comorbid conditions who need additional in-person screening assessments must provide 
informed consent remotely or in-person prior to undergoing the additional screening procedures. 
g Testing necessary to assess stability of comorbid diseases that may affect reaction to the vaccine. May include pulmonary function testing, chest X-
ray, electrocardiogram, echocardiogram, flexible nasolaryngoscopy, and/or blood laboratory testing.
h Study vaccinations will be administered in the Intensive Care Unit (ICU). The participant will be monitored for signs and symptoms of an 
allergic reaction and any other adverse event for a minimum of 3 hours after vaccination, and medications and equipment will be immediately 
available to treat possible reactions. The principal investigator and/or an experienced allergist associate investigator will be available. Day 2 
dosing may be delayed to a later day (maximum delay of 7 days) at the discretion of the investigator if the participant experiences an allergic 
reaction on day 1 that has not resolved by day 2.
i Only for participants receiving booster vaccination.  
j Participants (according to current FDA approvals/CDC guidelines) will be offered a booster dose of the Pfizer-BioNTech vaccine (monovalent or 
bivalent as described in section 4.1) at their 5-month visit (Visit 4) if they did not have a severe allergic reaction to the second dose in the ICU (ie, 
those who had CoFAR grade 2 reaction or less will be eligible for the booster). The booster vaccine will be administered in an outpatient clinic, 
and medications necessary to treat an allergic reaction, including epinephrine, will be readily available. Participants will be observed in the clinic 
for 2 hours after the booster dose is administered.
k Temperature, pulse rate, respiratory rate, oxygen saturation, and blood pressure will be measured within 30 minutes prior to each study 
vaccination, at the time of blood draws, and as clinically indicated following each study vaccination during Visit 1. Because participants will be in 
the ICU during Visit 1, many vital signs (e.g. pulse rate, respiratory rate) will be continuously monitored. At Visit 4, for participants who receive 
the booster dose, vital signs will be checked at baseline and prior to discharge, and as indicated in case of development of symptoms of an allergic 
reaction; otherwise, vital signs will be obtained per clinical routine at Visits 3 and 4.
l Performed prior to study vaccination on days 1 and 2. May be repeated during visit 1 and/or at follow-up visits at investigator discretion.

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m A nasal swab (mid-turbinate or nasopharyngeal per current Clinical Center practice) will be collected for SARS-CoV-2 testing by polymerase 
chain reaction. If the result is positive, Visit 1 will be delayed until the participant has recovered and is outside of the quarantine window.
n For participants of childbearing potential only. Must be confirmed negative prior to proceeding with study vaccination (at Visit 1) and booster 
dose (as applicable at Visit 4).
o Mental health history questionnaire, Impact of Events Scale-6, State-Trait Anxiety Inventory, Generalized Anxiety Disorder-7 scale, and World 
Health Organization Disability Assessment Schedule-2. Participants may be given informational materials to help manage stress.
p To be completed by English or Spanish speakers only. 
q May or may not be completed per investigator discretion.
r Completed pre- and post-dose.
s Mental health interview will take place via Clinical Center Microsoft Teams telehealth platform. Subjects will meet with a mental health clinician 
to review questionnaire results and be offered strategies to help manage distress. Subsequent sessions will be scheduled as needed based on 
ongoing reviews of mental health/anxiety assessments.
t During Visit 1, one void prior to each study vaccination and the first void after each study vaccination will be collected. If an allergic reaction 
occurs after the post-vaccination void is collected, an additional void may be collected. At Visit 4 (participants who opt in to booster dose only), 
one void prior to the booster dose and the first void post-dose prior to discharge will be collected, if possible.
u Blood samples will be collected from the IV line when possible; otherwise, venipuncture will be performed. During visit 1, samples will be 
collected before each study vaccination and approximately 35 minutes (+/-15 minutes), 2 hours (+/-30 minutes), 6 hours (+/-30 minutes), and 24 
hours (+/-1 hour) after each study vaccination. The 24-hour blood draw for day 1 will also serve as the baseline blood draw for day 2. At Visit 4, 
participants who do not receive a booster vaccination will undergo a single blood draw, and those who receive a booster vaccination may undergo 
blood draws pre-dose, 35 minutes (+/-15 minutes) post-dose, and 2 hours (+/-30 minutes) post-dose. 
v Will only be performed once, either at Visit 3 or Visit 4 per investigator discretion.
w If a participant develops a skin rash following vaccination, photographs of the affected area(s) may be taken with the participant’s permission.
x If the bivalent formulation (Original and Omicron BA.4/BA.5) of the vaccine is available at the NIH, participants will be given the option of 
receiving the bivalent or monovalent version as the booster dose; if the bivalent version is not available, the monovalent will still be offered. A 
consent addendum will be discussed with the participants about this choice.

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2
 INTRODUCTION
2.1
STUDY RATIONALE
Widespread vaccination will be essential to overcome the public health crisis created by COVID-
19. Although rare, the allergic reactions that have occurred as a result of COVID-19 mRNA 
vaccinations have created substantial fear and anxiety in the general population where allergic 
disease is common. This concern may translate to reduced willingness for patients with a history 
of severe allergies to receive the COVID-19 vaccine, and/or a hesitancy on the part of physicians 
to administer the vaccine to these patients out of concern that the vaccine will trigger an allergic 
reaction. Furthermore, the high rate of suspected allergic reactions following the initial doses of 
these vaccines may prevent a substantial fraction of the population from receiving a second dose, 
which may be necessary for the vaccine to be fully effective. Currently, the safety of 
administering a second dose of these vaccines to patients who experienced an allergic reaction to 
the first dose is unknown, as is the safety of administering a subsequent dose of an mRNA-based 
vaccine that is different than the one that caused a previous reaction (e.g., administering the 
Pfizer-BioNTech vaccine after a reaction to the Moderna vaccine). For these reasons, a better 
understanding of the mechanisms responsible for allergic reactions to the mRNA COVID 
vaccines is critically needed in order to reassure the public and to provide evidence-based 
guidance on who can safely receive these vaccines, including a second dose in those individuals 
who experienced a reaction to the first dose.
2.2
BACKGROUND 
Prevalence and characteristics of allergic reactions to messenger RNA (mRNA) vaccines for 
COVID-19
The SARS-CoV-2 virus has incited a global pandemic leading to profound loss of human life 
and tremendous economic and social upheaval. In late 2020, the FDA issued emergency use 
authorizations (EUAs) for monovalent mRNA vaccines produced by Pfizer-BioNTech and 
Moderna that were found to be highly effective in Phase 3 trials at preventing COVID-19.[1, 2] 
The active ingredient in both vaccines is nucleoside-modified mRNA encoding the SARS-CoV-2 
spike protein. The Pfizer-BioNTech monovalent COVID-19 vaccine, given as 2 doses 21 days 
apart, showed 95% efficacy at preventing symptomatic COVID-19 infection 7 days after 
administration of the second dose.[1] Protection from the vaccine was similar across different 
age, racial, and ethnic groups, and it received full FDA approval for individuals 16 years of age 
and older on August 23, 2021, under the brand name Comirnaty, with the eligible age group 
subsequently lowered to 12 years of age and older. As of September 16, 2022, it also continues 
to be available under EUA for individuals 6 months through 11 years of age and for the 
administration of a third primary dose in certain immunocompromised individuals. A previous 
authorization for use as a booster vaccination in individuals 12 years of age and older was 
removed when a new bivalent version was authorized for this use (see below). The Moderna 
monovalent COVID-19 vaccine, given as 2 doses 28 days apart, was 94% effective at preventing 
symptomatic infection 14 days after administration of the second dose.[2] The efficacy of the 
Moderna vaccine appeared to be slightly lower in people 65 years and older, but was equally 
effective across different racial and ethnic groups, and it received full FDA approval for people 
ages 18 years and older on January 31, 2022 under the brand name Spikevax, with authorizations 
for lower ages also anticipated. Both vaccines exhibited a favorable safety profile, with most side 

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effects being mild to moderate in severity and including pain, swelling, and redness at the 
injection site, headache, fatigue, fever, chills, nausea, myalgia, arthralgia, and lymphadenopathy. 
However, within days of administration of the vaccines to healthcare workers in both the United 
States (US) and United Kingdom (UK), multiple reports of severe allergic reactions emerged. As 
of January 18, 2021, 47 cases of anaphylaxis (defined by Brighton Collaboration case definition 
criteria 1, 2, or 3 as assessed by Centers for Disease Control and Prevention [CDC] 
physicians)[3] attributed to the Pfizer-BioNTech vaccine, and 19 cases attributed to the Moderna 
vaccine, had been reported to the CDC/FDA Vaccine Adverse Event Reporting System 
(VAERS).[4] In nearly all cases (89% for both vaccines), symptoms appeared within 30 minutes 
of vaccine administration, and nearly all cases were in women (94% for Pfizer-BioNTech and 
100% for Moderna). Most reactions (92%) were treated with epinephrine. Forty-eight percent of 
the individuals who experienced reactions were hospitalized (7 of whom required endotracheal 
intubation). The vast majority of individuals who experienced post-vaccine anaphylaxis had a 
documented history of severe allergies and/or allergic reactions to drugs, foods, insect stings, 
contrast media, and/or vaccines (77% of those who reacted to the Pfizer-BioNTech vaccine and 
84% of those who reacted to the Moderna vaccine). As of January 18, 2021, the overall rate of 
anaphylaxis to the mRNA COVID-19 vaccines was estimated at 4.7 cases per million doses 
administered for the Pfizer-BioNTech vaccine and 2.5 cases per million doses administered for 
the Moderna vaccine.[4] This rate of anaphylaxis is higher than that reported for vaccines in 
general, which is 1.31 (95% CI, 0.90-1.84) cases per million vaccine doses, using similar criteria 
for defining anaphylaxis.[5] Of note, the rate of reported allergic reactions to the mRNA 
COVID-19 vaccines, including both mild-moderate and severe reactions, is significantly higher 
than 2.8-5.0 cases per million doses. However, the CDC found that nearly half of reported severe 
“allergic” reactions to the mRNA vaccines could not be confirmed after case review, 
emphasizing the importance of a thorough allergy evaluation in assessing vaccine reactions and 
the need for challenge studies to confirm and investigate the mechanisms responsible. As of 
January 2021, there were no fatalities associated with reported allergic reactions to either the 
Pfizer-BioNTech or Moderna vaccines.[4]
FDA granted an EUA on August 31, 2022, for the use of a bivalent version of the Pfizer-
BioNTech vaccine (referred to as Pfizer-BioNTech COVID-19 Vaccine, Bivalent [Original and 
Omicron BA.4/BA.5]) as a booster vaccination. Subsequently, CDC updated their 
recommendation on September 1, 2022, as follows: “People ages 12 years and older are 
recommended to receive 1 age-appropriate bivalent mRNA booster dose after completion of any 
FDA-approved or FDA-authorized monovalent primary series or previously received 
monovalent booster dose(s). This new booster recommendation replaces all prior booster 
recommendations for this age group.”[6] These recommendations were made after favorable vote 
from CDC’s Advisory Committee on Immunization Practices (ACIP). The evidence was based 
primarily on the results of serological data against BA.1 variant and pre-clinical serological 
assessment using BA.4/BA.5 variant demonstrating superior neutralization antibody titers. These 
titers were noted to exceed pre-defined non-inferiority criteria against all Omicron variants, in 
particular BA.4/5, with the use of a bivalent booster dose including the original strain and 
Omicron BA.4/5. Reactogenicity was noted to be comparable to the original vaccine.[7, 8] These 
data were used to predict likely favorable outcomes by greater serological protection against 
Omicron variants. Other animal model studies noted similar enhancement in neutralizing 

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antibody titers after variant-based vaccination.[9, 10] Another study used a predictive model to 
estimate the benefit after use of variant-based modified vaccine and estimated that the efficacy of 
the modified vaccine was similar against severe disease while likely offering 4.6% more 
protection against symptomatic infection compared to the traditional vaccine’s estimated 
protection at 85.6%, and hence was estimated to cause 8 less infections per 1000 population.[11, 
12] At this time, the evidence is largely pre-clinical with extrapolation to the real-world scenario 
with assumption that the updated booster will likely offer improved protection against Omicron 
variants. Similarly, at this time it is unknown if there will be any difference in incidence of AEs 
such as anaphylaxis, myocarditis, and others, and the risk is presumed to be similar to the 
original (monovalent) vaccine. However, further clinical data is needed to confirm real-time 
efficacy and safety. While not in line with the current FDA authorizations and CDC guidelines, 
booster vaccination with the the monovalent version of the vaccine would still provide valuable 
scientific information for the purposes of this study, and will will likely continue to provide 
protection against severe COVID-19 illness if used as a booster vaccine in remaining subjects.
According to current FDA and CDC recommendations, individuals with a history of an 
anaphylactic reaction to any component of the mRNA COVID-19 vaccines should not receive 
these vaccines. Individuals with a history of an immediate allergic reaction to a vaccine or 
injectable or any history of anaphylaxis should be observed for 30 minutes post-vaccination, and 
all other individuals should be observed for 15 minutes. Additionally, patients who have an 
immediate (within 4 hours) or severe allergic reaction (e.g., anaphylaxis) to either mRNA 
COVID-19 vaccine are currently advised not to receive a second dose. 
Immunologic and nonimmunologic mechanisms can trigger anaphylactic reactions 
Anaphylaxis is a rapidly developing, life-threatening, systemic allergic reaction. Classically, 
anaphylaxis is caused by a type I hypersensitivity reaction where exposure to an antigen induces 
cross-linking of antigen-specific IgE bound to the high affinity IgE receptor, FcRI, on the 
surface of mast cells and basophils. This triggers cellular degranulation and the release of pre-
formed mediators, including histamine and preformed cytokines, tryptase, and other proteases, as 
well as synthesis and secretion of additional cytokines and lipid mediators including platelet 
activating factor (PAF), leukotrienes, and prostaglandins. The release of these mediators is 
responsible for the clinical signs and symptoms of an allergic reaction, including flushing, 
pruritus, rhinorrhea, tachycardia, bronchospasm, increased vascular permeability, and 
hypotension.
Although IgE-dependent mast cell degranulation is the most commonly recognized cause of 
anaphylaxis, multiple other mechanisms, both immunologic and non-immunologic in nature, can 
result in identical clinical presentations. In mice, IgG can also trigger anaphylaxis as a result of 
antigen-IgG binding to the FcRIII on basophils, macrophages, and neutrophils, leading to the 
release of PAF that triggers an increase in vascular permeability and hypotension.[13] IgG-
mediated anaphylaxis has not been definitively proven in humans, but some studies have found 
PAF to be an important mediator of anaphylaxis in patients.[14, 15] Activation of the 
complement pathway can also trigger symptoms of anaphylaxis through the release of C3a, C5a, 
and soluble C5b-C9 (sC5b-C9), which can bind to their receptors on mast cells, basophils, and 
other myeloid cells and stimulate degranulation.[16-18] Depletion of complement proteins and 
production of C3a and C5a have been seen both in murine models of anaphylaxis and in clinical 

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studies.[19] Additionally, mediators released from mast cells, including heparin, can also 
activate factor XII (FXII) and the pro-inflammatory kallikrein–kinin system that results in the 
release of the mediator bradykinin (BK). Some studies have found that levels of BK, which 
triggers vasodilation and an increase in vascular permeability, correlate with the severity of 
anaphylaxis.[20] 
In some cases, anaphylaxis is induced via non-immunologic mechanisms as a result of the direct 
activation of mast cells.[21] For example, certain drugs, including opioids, dextrans, and 
quinolones, can directly stimulate mast cells and/or interact with the MAS-related G protein-
coupled receptor-X2 (MRGPRX2) on mast cells, triggering their degranulation.
Finally, a number of conditions can masquerade as anaphylaxis, including vasovagal reactions, 
pain, and anxiety, which can be associated with flushing, pallor, shortness of breath, tachycardia, 
lightheadedness, and throat tightness. 
Potential mechanisms underlying severe, immediate allergic reactions to COVID-19 mRNA 
vaccines 
The Pfizer-BioNTech and Moderna vaccines utilize a liposomal-based drug delivery system to 
prevent degradation of the mRNA cargo and to facilitate delivery to target cells, although the 
lipids used in the 2 vaccines differ slightly (see Table 1). Both vaccine preparations also contain 
the excipient PEG 2000, which is conjugated to the lipids to improve water solubility, prevent 
aggregation, and provide increased stability and a longer half-life. While mRNA vaccines have 
been studied for some time, the current COVID-19 mRNA vaccines were the first to receive 
EUA, and the Pfizer-BioNTech product is the first to be licensed. These vaccines are also the 
first to use PEG. PEG has been hypothesized to be the antigenic trigger responsible for allergic 
reactions to the COVID-19 mRNA vaccines, but currently there is no direct evidence to support 
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Table 1: Composition of Pfizer-BioNTech COVID-19 Vaccine and Moderna COVID-19 
Vaccine
Pfizer-BioNTech COVID-19 Vaccine
Moderna COVID-19 Vaccine
Active 
Nucleoside-modified messenger RNA 
(modRNA) encoding the viral spike (S) 
glycoprotein of SARS-CoV-2. 
Nucleoside-modified mRNA encoding the 
prefusion stabilized spike (S) glycoprotein of 
SARS-CoV- 2 
((4-hydroxybutyl)azanediyl)bis(hexane- 
6,1diyl)bis(2-hexyldecanoate) 
SM-102 (Proprietary to Moderna) 
2[(polyethylene glycol [PEG] 2000)]-N,N-
ditetradecylacetamide 
Polyethylene glycol (PEG) 
2000 dimyristoyl glycerol (DMG) 
1,2-distearoyl-sn-glycero-3- 
phosphocholine 
1,2-distearoyl-sn-glycero-3- 
phosphocholine 
Inactive – lipids 
Cholesterol 
Cholesterol 
Tromethamine, tromethamine 
hydrochloride
Tromethamine, Tromethamine hydrochloride, 
acetic acid, sodium acetate 
Inactive – salts, 
sugars, buffers 
Sugar (sucrose) 
Sugar (sucrose) 
PEG is a very common ingredient found in a wide variety of commercial products including 
more than 1000 FDA-approved medications and over-the-counter products including skin 
creams, cosmetics, sunscreen, toothpaste, shampoo, and foods. PEG has notoriously been 
considered very safe, although rare allergic reactions have been reported. A review of FDA 
records from 2005 through 2017 identified an average of 4 cases (range, 2-8 cases) per year of 
PEG-associated anaphylaxis, typically following ingestion of PEG in colonoscopy preparations 
(Golytely) or treatments for constipation (Miralax).[22] A recent study found that at least some 
cases of PEG-associated anaphylaxis are caused by type I hypersensitivity reactions triggered by 
PEG-specific IgE. This study also screened for preexisting anti-PEG antibodies in sera from 
“normal” donors using a Dual Cytometric Bead Assay (DCBA). Up to 9% of samples were 
positive for anti-PEG IgG, 6% for anti-PEG IgM, and 0.1% for anti-PEG IgE.[23] In a separate 
study, Chang et al. discovered 7 single-nucleotide polymorphisms (SNPs) localized in the 
variable segment of immunoglobulin heavy chain gene that were significantly associated with 
high prevalence and concentrations of anti-PEG IgM in the general population in China.[24] This 
study therefore suggests that host genetic factors may contribute to PEG immunogenicity.
Although PEGylated liposomes are often considered nonimmunogenic, use of these preparations 
has been associated with the development of anti-PEG IgM and IgG antibodies that can instigate 
accelerated blood clearance of pegylated drugs (ABC phenomenon) and acute hypersensitivity 
reactions, termed Complement Activation Related Pseudoalleregy (CARPA).[25, 26] Both types 
of adverse reactions are thought to be driven by complement activation. In a pig model, delivery 
of 2-K-methoxy-PEGylated liposomes induced a strong anti-PEG IgM response that triggered 
fatal anaphylaxis as a result of complement pathway activation, as indicated by elevation of the 

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terminal complement complex (sC5b-9) in the blood of affected animals.[27] In the case of 
PEGylated liposomes harboring an mRNA payload, the immunostimulatory properties of the 
nucleic acid could further promote an immune response to PEG.
PEG shares significant structural similarity with polysorbate 80, which is found in several 
currently licensed vaccines and is a rare cause of vaccine allergic reactions.[22] Many of the 
COVID-19 vaccines currently under development that are using a platform distinct from the 
mRNA/PEGylated liposomes do not contain PEG but do contain polysorbate 80. Because of the 
potential cross-reactivity between PEG and polysorbate 80, individuals who have experienced a 
severe allergic reaction to the mRNA vaccines may be advised to avoid all polysorbate 80-
containing injectables until a role for PEG in these reactions has been ruled out. 
2.3
RISK/BENEFIT ASSESSMENT
2.3.1
Known Potential Risks
Vaccines: The risks of the Pfizer-BioNTech COVID-19 vaccines are detailed in the full FDA 
prescribing information documents.[28, 29] The most common adverse reactions following the 
Pfizer-BioNTech COVID-19 vaccines that have been reported in clinical trials include injection 
site pain, fatigue, headache, muscle pain, chills, joint pain, fever, injection site swelling, and 
injection site redness. Other side effects included nausea, malaise, lymphadenopathy, diarrhea, 
vomiting, and arm pain as well as asthenia, lethargy, decreased appetite, hyperhidrosis, night 
sweats, or rash. Fainting can happen from any vaccine given by injection.
Postmarketing data demonstrate increased risks of myocarditis and pericarditis, particularly 
within 7 days following the second dose. The observed risk is higher among males under 40 
years of age than among females and older males. The observed risk is highest in males 12 
through 17 years of age. Although some cases required intensive care support, available data 
from short-term follow-up suggest that most individuals have had resolution of symptoms with 
conservative management. Information is not yet available about potential long-term sequelae. 
The CDC has published considerations related to myocarditis and pericarditis after vaccination, 
including for vaccination of individuals with a history of myocarditis or pericarditis 
(https://www.cdc.gov/vaccines/covid-19/clinical-considerations/myocarditis.html). Individuals 
with a history of myocarditis or pericarditis may undergo additional screening procedures to 
assess for increased risk for these events following vaccination, and may be excluded from 
participation at the discretion of the investigator.
Severe allergic reactions have also been reported following the Pfizer-BioNTech monovalent 
vaccine during mass vaccination outside of clinical trials. Because the participants in this trial 
have previously experienced a systemic allergic reaction following administration of the Pfizer-
BioNTech or Moderna vaccine, they are likely to be at higher risk for experiencing a second 
allergic reaction upon rechallenge with the mRNA-based Pfizer-BioNTech vaccine compared to 
the general population. Allergic reactions can range from mild to severe, with symptoms such as 
hives, and can include life-threatening anaphylactic reactions, with symptoms such as swelling of 
the airways, breathing difficulties, and low blood pressure. If a participant has an allergic 
reaction, they may need oral, intramuscular, or intravenous medications. Medications and 
equipment will be immediately available to treat possible reactions. Allergic reactions can also 
cause emotional distress. 

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The placebo vaccine does not contain active ingredients, and there are no known risks. However, 
since the participants in this study experienced allergic reactions to their first vaccine dose, they 
may experience increased anxiety, which may bring on symptoms similar to an allergic reaction.
Skin prick and intradermal testing: Skin testing is a standard medical procedure that rarely leads 
to complications. The procedure may lead to mild itching and swelling of the skin that is self-
limited, subsides within 1-2 hours, and leaves no permanent mark on the skin. Anaphylaxis as a 
result of allergen skin testing is exceedingly rare and nearly always associated with intradermal 
testing without prior prick/puncture testing. For this reason, intradermal testing will only be 
performed after negative prick/puncture testing. Medications for treatment of anaphylaxis will be 
available on the unit and a physician in the hospital when skin testing is performed. Participants 
will stay in the clinic for 30 minutes after the skin testing to monitor for anaphylaxis.
Intravenous (IV) line insertion and venipuncture: Insertion of IV lines and venipuncture may 
cause pain, bruising, lightheadedness, dizziness, possible fainting, local discomfort, uncontrolled 
bleeding, and, rarely, infection at the site where the needle is inserted.
Nasal swab collection: Nasal swab collection may cause localized discomfort. Rarely, mild 
epistaxis may occur.
Clinical photography: Taking pictures of the face and body may be embarrassing to some people. 
These photographs may be published in medical journals, without identifying the participant. We 
will attempt to preserve the anonymity of the participant as much as possible, while providing 
the information needed to support the research being published. Participants may decline 
photographs or place any restrictions on their use. Participants will be given the opportunity to 
discuss this with the principal or associate investigators.
Pulmonary function testing: Risks of pulmonary function tests include possible fainting or light-
headedness due to hyperventilation or, rarely, an asthmatic episode precipitated by deep 
inhalation exercises.
Peak flow measurement and impulse oscillometry: A sterile filter is used to prevent any risk 
associated with oral contact to the machines. Otherwise there are no associated risks with this 
testing procedure.
Chest X-ray: The risk associated with a single chest X-ray is exposure to a low level of radiation 
(<0.3 rem).
Echocardiogram and electrocardiogram (ECG): Other than possible minor skin irritation from 
the electrodes, there are no anticipated risks related to these procedures.
Flexible nasolaryngoscopy: Risks of flexible nasolaryngoscopy include a strange sensation as the 
scope is inserted into the nose and, rarely, nosebleed.
Urine collection: There are no risks associated with urine sample collection.

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Mental health evaluations: The mental health evaluations will involve serial mental health 
questionnaires and surveys of topics such as anxiety and mood symptoms, as well as clinical 
interviews. The risks associated with the questionnaires and clinical interviews are minimal, 
beyond transient increases in stress associated with difficult topics. The questionnaires require a 
minimal amount of time to complete (up to 20 minutes total). Results will be maintained 
securely, but there is a slight risk of loss of confidentiality of information collected in the 
questionnaires. The interviews will be conducted by a mental health clinician who can follow-up 
on clinically significant issues. It is possible a participant may report high levels of mental health 
symptoms, onset of new symptoms, or show trends in worsening of symptoms that could indicate 
a need for mental health care. If there is a question of participant safety or a harm to others (e.g., 
suicidal ideation) a consultation to the National Institute of Mental Health Psychiatric 
Consultation Liaison Service will be requested. At a minimum, information about national and 
local mental health resources, such as hotlines, and guidance on steps to take to seek care in the 
community will be provided for any individual who could benefit.
2.3.2
Known Potential Benefits
Participants in this trial may benefit by receiving a second dose (and potentially a booster dose) 
of an mRNA-based COVID-19 vaccine (which they otherwise would not receive) in an 
environment where the investigators and staff are experienced in the care of patients with 
anaphylactic reactions, and all equipment and medications necessary to treat severe reactions 
will be readily available. The information gained in the study will improve the understanding of 
the mechanisms underlying allergic reactions to mRNA COVID-19 vaccines and support the 
creation of evidence-based guidance on who can safely receive these vaccines, including a 
second dose in individuals who experienced a reaction to the first dose, whether the second dose 
is the same or a discordant mRNA-based vaccine as that of the first dose, as well as a booster 
dose. 
2.3.3
Assessment of Potential Risks and Benefits
In a case series study of 159 patients, including 19 who met anaphylaxis criteria after the first 
dose of an mRNA COVID-19 vaccine, all 159 patients tolerated the second dose.[30] Thirty-two 
(20%) reported immediate and potentially allergic symptoms that were associated with the 
second dose that were self-limited, mild, and/or resolved with antihistamines alone. However, 
individuals who experience a systemic allergic reaction following the first dose of the Pfizer-
BioNTech or Moderna vaccines are advised not to receive a second dose according to current 
FDA and CDC guidelines. Although the efficacy of a single dose of these vaccines has not been 
systematically studied, 2 doses of the vaccine may be necessary for full efficacy. Whether a 
second dose with a discordant vaccine from that given as the first dose is as effective as receipt 
of the same vaccine for both doses is unknown. Because of the potential role for PEG as the 
culprit trigger for these allergic reactions, these individuals may also be advised to avoid any 
new COVID-19 vaccines under development that contain PEG or the cross-reactive polysorbate 
80, limiting their access to vaccines that protect against COVID-19. Clarification of the 
mechanisms underlying allergic reactions in this population will facilitate risk factor analysis to 
improve patient selection for these vaccines and potentially improve the design of future 
vaccines using this platform.

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To maximize safety, all participants will be admitted to the Intensive Care Unit (ICU) at the 
Clinical Center for visit 1, where experienced staff and all equipment and medications necessary 
to treat severe allergic reactions are readily available. Participants receiving a booster 
vaccination at visit 4 will be monitored closely for at least 2 hours after administration, with 
staff, equipment, and medications readily available in case of an allergic reaction. Patients will 
also be screened by phone prior to enrollment to ensure that other comorbid conditions (e.g. 
asthma) that may increase the risk of a severe reaction are stable. If sufficient information cannot 
be obtained over the phone, or additional testing (e.g., pulmonary function tests) is felt to be 
necessary to make this assessment, potential subjects may be asked to come to the NIH for 
additional testing before enrollment.
3
OBJECTIVES AND ENDPOINTS
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
Primary
1.
Assess the proportion of 
participants who develop a 
systemic allergic reaction 
(Consortium for Food Allergy 
Research [CoFAR; see 
Appendix A] grade 2 reaction 
and above regardless of 
tryptase, or CoFAR grade 1 
with elevated tryptase [1.2 X 
baseline plus 2ng/mL]) to the 
Pfizer-BioNTech COVID-19 
vaccine after previously 
demonstrating a systemic 
allergic reaction (CoFAR Grade 
2 or 3 reaction regardless of 
tryptase OR Grade 1 reaction 
with elevated tryptase [1.2 X 
baseline plus 2ng/mL]) to their 
first full dose of the same 
vaccine or the Moderna 
COVID-19 vaccine.
1.
The proportion of participants 
who previously demonstrated a 
systemic allergic reaction 
(CoFAR Grade 2 or 3 reaction 
regardless of tryptase OR 
Grade 1 reaction with elevated 
tryptase [1.2 X baseline plus 
2ng/mL]) to their first full dose 
of the Pfizer-BioNTech or 
Moderna COVID-19 vaccine 
who experience a systemic 
allergic reaction (CoFAR 
Grade 2 and above reaction 
regardless of tryptase, or 
CoFAR grade 1 with elevated 
tryptase [1.2 X baseline plus 
2ng/mL]) within the 3-hour 
post-vaccine observation 
period to a subsequent dose of 
the Pfizer-BioNTech vaccine.
This endpoint was chosen 
since it will provide critical 
information regarding the 
safety of administering a 
dose of the Pfizer-
BioNTech mRNA COVID-
19 vaccine to individuals 
who experienced a previous 
allergic reaction to an 
mRNA-based COVID-19 
vaccine. This information 
will be helpful in guiding 
public policies for these 
patients.
Secondary
1.
Assess the proportion of 
participants who develop a 
severe systemic allergic 
reaction (CoFAR Grade 3 
reaction or higher regardless of 
tryptase) to the Pfizer-
BioNTech COVID-19 vaccine 
after previously demonstrating a 
systemic allergic reaction 
(CoFAR Grade 2 or 3 reaction 
1.
The proportion of participants 
who previously demonstrated a 
systemic allergic reaction 
(CoFAR Grade 2 or 3 reaction 
regardless of tryptase OR 
Grade 1 reaction with elevated 
tryptase [1.2 X baseline plus 
2ng/mL]) to their first full dose 
of the Pfizer-BioNTech or 
Moderna COVID-19 vaccine 
These endpoints were 
chosen as they will inform 
the severity of allergic 
reactions that may be 
experienced following 
administration of a dose of 
the Pfizer-BioNTech 
mRNA COVID-19 vaccine 
to individuals who 
experienced an allergic 

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OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
regardless of tryptase OR Grade 
1 reaction with elevated tryptase 
[1.2 X baseline plus 2ng/mL]) 
to their first full dose of the 
same vaccine or the Moderna 
COVID-19 vaccine.
2.
Assess the proportion of 
participants who develop a 
mild-moderate allergic 
reaction (CoFAR Grade 1 or 2 
reaction regardless of tryptase) 
to the Pfizer-BioNTech 
COVID-19 vaccine after 
previously demonstrating a 
systemic allergic reaction 
(CoFAR Grade 2 or 3 reaction 
regardless of tryptase OR Grade 
1 reaction with elevated tryptase 
[1.2 X baseline plus 2ng/mL]) 
to their first full dose of the 
same vaccine or the Moderna 
COVID-19 vaccine.
3.
Assess the proportion of 
participants with anaphylactic 
reactions (Levels 1-3) per 
Brighton Collaboration Criteria 
(see Appendix B) to the Pfizer-
BioNTech COVID-19 vaccine 
after previously demonstrating a 
systemic allergic reaction 
(CoFAR Grade 2 or 3 reaction 
OR Grade 1 reaction with 
elevated tryptase [1.2 X 
baseline plus 2ng/mL]) to their 
first full dose of the same 
vaccine or the Moderna 
COVID-19 vaccine.
who experience a severe 
systemic allergic reaction 
(CoFAR grade 3 reaction and 
above) within the 3-hour post-
vaccine observation period to a 
subsequent dose of the Pfizer-
BioNTech vaccine.
2.
The proportion of participants 
who previously demonstrated a 
systemic allergic reaction 
(CoFAR Grade 2 or 3 reaction 
regardless of tryptase OR 
Grade 1 reaction with elevated 
tryptase [1.2 X baseline plus 
2ng/mL]) to their first full dose 
of the Pfizer-BioNTech or 
Moderna COVID-19 vaccine 
who experience a mild-
moderate allergic reaction 
(CoFAR grade 1 or 2 reaction 
regardless of tryptase) within 
the 3-hour post-vaccine 
observation period to a 
subsequent dose of the Pfizer-
BioNTech vaccine.
3.
The proportion of participants 
who previously demonstrated a 
systemic allergic reaction 
(CoFAR Grade 2 or 3 reaction 
regardless of tryptase OR 
Grade 1 reaction with elevated 
tryptase [1.2 X baseline plus 
2ng/mL]) to their first full dose 
of the Pfizer-BioNTech or 
Moderna COVID-19 vaccine 
who experience an 
anaphylactic reaction (Levels 
1-3) per Brighton 
Collaboration Criteria within 
the 3-hour post-vaccine 
observation period to a 
subsequent dose of the Pfizer-
BioNTech vaccine.  
reaction to an initial dose of 
an mRNA-based COVID-
19 vaccine, allow 
comparison of our data to 
other proposed and ongoing 
studies evaluating the 
safety of the Pfizer-
BioNTech COVID-19 
vaccine in individuals 
potentially at high risk for 
allergic reactions to the 
vaccine, as well as 
comparison to data 
collected by the CDC.

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OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
4.
Assess the proportion of 
participants who develop a 
systemic allergic reaction 
(CoFAR Grade 2 reaction or 
higher regardless of tryptase OR 
Grade 1 reaction with elevated 
tryptase [1.2 X baseline plus 
2ng/mL]) to the Pfizer-
BioNTech COVID-19 vaccine 
after previously demonstrating a 
systemic allergic reaction 
(CoFAR Grade 2 or 3 reaction 
regardless of tryptase OR Grade 
1 reaction with elevated tryptase 
[1.2 X baseline plus 2ng/mL]) 
to their first full dose of the 
same vaccine or the Moderna 
COVID-19 vaccine compared to 
the rate of these reactions 
following placebo 
administration.
5.
Compare the severity of allergic 
reactions to the first dose of the 
Pfizer-BioNTech or Moderna 
COVID-19 vaccine to the 
severity of the reaction 
following administration of a 
subsequent dose of the Pfizer-
BioNTech vaccine in 
individuals who experienced a 
systemic allergic reaction 
(CoFAR grade 2 reaction and 
above regardless of tryptase, or 
CoFAR grade 1 with elevated 
tryptase [1.2 X baseline plus 
2ng/mL]) to their first full dose 
of the Pfizer-BioNTech or 
Moderna COVID-19 vaccine.
4.
The proportion of participants 
who previously demonstrated a 
systemic allergic reaction 
(CoFAR Grade 2 or 3 reaction 
regardless of tryptase OR 
Grade 1 reaction with elevated 
tryptase [1.2 X baseline plus 
2ng/mL]) to their first full dose 
of the Pfizer-BioNTech or 
Moderna COVID-19 vaccine 
who experience a systemic 
allergic reaction (CoFAR 
grade 2 reaction and above 
regardless of tryptase, or 
CoFAR grade 1 with elevated 
tryptase [1.2 X baseline plus 
2ng/mL]) within the 3-hour 
post-vaccine observation 
period to a subsequent dose of 
the Pfizer-BioNTech vaccine 
compared to the rate of these 
reactions following placebo 
administration.
5.
The proportion of participants 
who previously demonstrated a 
systemic allergic reaction 
(CoFAR Grade 2 or 3 reaction 
regardless of tryptase OR 
Grade 1 reaction with elevated 
tryptase [1.2 X baseline plus 
2ng/mL]) to their first full dose 
of the Pfizer-BioNTech or 
Moderna COVID-19 vaccine 
who develop a lower or higher 
grade allergic reaction within 
the 3-hour post-vaccine 
observation period to a 
subsequent dose of the Pfizer-
BioNTech vaccine.
Tertiary/Exploratory 
1.
Assess the risk of having a 
systemic allergic reaction to a 
dose of the Pfizer-BioNTech 
COVID-19 vaccine in 
1.
Prevalence of polyethylene 
glycol (PEG) and SARS-CoV-
2 antibodies in each participant 
at baseline.
In order to determine which 
individuals are at high risk 
for having an allergic 
reaction to the mRNA 

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OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
participants who previously 
demonstrated a systemic 
allergic reaction (CoFAR Grade 
2 or 3 reaction regardless of 
tryptase OR Grade 1 reaction 
with elevated tryptase [1.2 X 
baseline plus 2ng/mL]) to their 
first full dose of the same 
vaccine or the Moderna 
COVID-19 according to 
baseline covariates.
2.
Examine possible mechanisms 
of allergic reactions to mRNA-
based COVID-19 vaccines. 
3.
Assess innate and adaptive 
immune responses, including 
functional antibody levels, to 
the Pfizer-BioNTech COVID-
19 vaccine.
4.
Investigate mental health 
characteristics of participants 
who experience an allergic 
reaction to the COVID-19 
vaccine.
5.
Assess psychological impact of 
allergic reactions to the 
COVID-19 vaccine and 
examine changes in stress levels 
over time.
6.
Assess anxiety levels in 
participants and examine 
changes in anxiety over time.
7.
Assess the proportion of 
participants who experience no 
reaction or only a mild reaction 
(CoFAR Grade 2 or below) to a 
booster dose of the Pfizer-
BioNTech vaccine after 
previously demonstrating a 
systemic allergic reaction 
(CoFAR Grade 2 or 3 reaction 
regardless of tryptase OR Grade 
2.
Changes in anti-PEG and 
SARS-CoV-2 antibodies in 
each participant approximately 
1 and 5 months after receiving 
the dose of the Pfizer-
BioNTech vaccine 
administered on study.
3.
Prevalence of positive skin 
testing to the vaccine and/or 
vaccine components including 
PEG- and polysorbate 80-
containing medications. 
4.
Changes in biomarkers from 
baseline to post-dose of the 
Pfizer-BioNTech vaccine 
administered on study (e.g., 
known mediators of systemic 
reactions due to mast cell 
activation, markers of 
inflammatory response, 
markers of basophil and 
neutrophil activation, markers 
associated with activation of 
the classical and alternative 
complement pathways or kinin 
system, proteomics, 
metabolomics).
5.
Changes in blood 
transcriptomics after 
vaccination.
6.
Changes in innate and adaptive 
immune responses, including 
functional antibody levels, 
after vaccination.
7.
Mental health/anxiety 
questionnaire scores and 
anxiety level ratings at 
baseline.
8.
Results of psychiatric 
consultation/mental health 
interview.
COVID-19 vaccines, and 
which patients who 
experienced an allergic 
reaction to the initial dose 
can safely receive a second 
dose, a better understanding 
of the mechanisms driving 
allergic reactions to these 
vaccines is needed. These 
endpoints will provide 
insight into the cellular and 
immunologic pathways that 
are driving allergic 
reactions to these vaccines. 
Additionally, a better 
understanding of the impact 
of administering a second 
dose of the vaccine to 
individuals who 
experienced an allergic 
reaction to the first dose on 
mental health and anxiety 
levels will provide valuable 
information to clinicians 
caring for these patients.
Data collected from 
participants who receive a 
5-month booster on this 
study will provide 
additional information 
regarding the safety of 
administering booster doses 
of the Pfizer-BioNTech 
vaccine to patients who 
experienced a systemic 
allergic reaction to the first 
dose of the COVID-19 
mRNA vaccines but who 
tolerated the second dose 
with only mild or no 
allergic symptoms. This 
information will have 
important public health 
implications given the need 
for boosters now and in the 
future in order to achieve 
full protection against 

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OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
1 reaction with elevated tryptase 
[1.2 X baseline plus 2 ng/mL]) 
to their first full dose of the 
Pfizer-BioNTech or Moderna 
COVID-19 vaccine and no 
allergic reaction or a mild 
reaction (CoFAR Grade 2 or 
below) to a subsequent (second) 
dose of the Pfizer-BioNTech 
vaccine.
8.  Assess the development of     
autoantibodies after COVID-19 
vaccination.
9.
Changes in mental 
health/anxiety questionnaire 
scores and anxiety level ratings 
over the study period.
10. The proportion of participants 
who previously demonstrated a 
systemic allergic reaction 
(CoFAR Grade 2 or 3 reaction 
regardless of tryptase OR 
Grade 1 reaction with elevated 
tryptase [1.2 X baseline plus 2 
ng/mL]) to their first full dose 
of the Pfizer-BioNTech or 
Moderna COVID-19 vaccine 
and no allergic reaction or a 
mild reaction (CoFAR Grade 2 
or below) to a subsequent 
(second) dose of the Pfizer-
BioNTech vaccine who 
experience no reaction or only 
a mild reaction (CoFAR Grade 
2 or below) to a booster dose 
of the Pfizer-BioNTech 
vaccine administered 
approximately 5 months after 
the second dose.
11. The development of 
autoantibodies post-second and 
post-booster doses of the 
COVID-19 mRNA vaccines.
COVID-19, and to provide 
reassurance to allergists and 
other medical professionals 
caring for these patients 
that they can safely 
administer booster doses to 
these patients in an 
outpatient setting.
4
STUDY DESIGN
4.1
OVERALL DESIGN
This will be a single-site study that will be performed at the NIH CC. The goal is to enroll up to 
100 subjects, although we may not be able to reach that target. There is great uncertainty about 
the number of individuals with systemic allergic reactions, along with the acceptability of these 
individuals of repeat vaccination and a 4-day inpatient stay. The study will provide more precise 
estimates with greater enrollment; however, even if fewer than 100 subjects enroll, this will 
provide very valuable new information. The study population will consist of individuals 16-69 
years of age who experienced a systemic allergic reaction, based on review of their history and 
medical records, to their first full dose of the Pfizer-BioNTech or Moderna COVID-19 vaccines.

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Prior to enrollment, participants will be screened remotely by phone/email and/or 
videoconference (using an NIH-approved platform) to assess eligibility and to ensure co-morbid 
allergic and other diseases, including asthma and atopic dermatitis, are well-controlled and 
disease activity is stable. If individuals have co-morbid conditions that may increase their risk of 
having a severe allergic reaction, they may be asked to come to the NIH CC for additional 
studies, such as pulmonary function testing, echocardiogram, or blood laboratory testing, that are 
felt to be clinically necessary (based on the discretion of the study team) to ensure that they are 
medically stable to undergo the study intervention. After screening, eligible individuals will be 
enrolled and admitted to the NIH CC ICU on day 0. Two IV lines will be inserted prior to study 
vaccination to allow for frequent blood draws and rapid administration of fluids/medications if 
needed in the event of a reaction. We will aim to admit subjects so that their first study 
vaccination occurs as close as possible to when the second dose of vaccine is indicated (i.e., 21 
days after the first dose of the Pfizer-BioNTech vaccine and 28 days after the first dose of the 
Moderna vaccine), but since the goal of this study is to assess allergic reactions and not provide 
clinical vaccinations as indicated, subjects may be enrolled regardless of time elapsed since their 
initial vaccination. On day 1, they will be randomized at a 1:1 ratio to receive either placebo or 
the Pfizer-BioNTech vaccine. A pre-vaccination blood and urine sample will be obtained, and 
then the first dose (per randomization) of study vaccine will be given. Serial blood draws and the 
first void (urine) after the dose will be collected. Another post-vaccination void may be collected 
if an allergic reaction occurs after the first collection. The participant will be monitored by the 
principal investigator and/or an experienced allergist associate investigator for signs and 
symptoms of an allergic reaction and any other AE for a minimum of 3 hours, and medications 
and equipment will be immediately available to treat possible reactions. If a reaction does 
develop, the participant will be treated according to our study MOP, and additional urine samples 
may be collected to assess the immune response. If a skin rash develops, photographs may be 
taken to document variations in presentation. In case of a reaction after the first dose, the 
participant will be counseled and the second study vaccination will proceed as scheduled if the 
participant is willing. On day 2, the participant will receive either placebo or the Pfizer-
BioNTech vaccine (whichever was not given on day 1) using the same procedure, but in the 
opposite arm. The participant will be monitored and treated (as needed) for an allergic reaction 
or AEs and samples will be collected as described for day 1. Participants will be discharged on 
day 3, unless they require additional treatment due to a reaction. Additionally, day 2 dosing may 
be delayed to a later day at the discretion of the investigator if the participant experiences an 
allergic reaction on day 1 that has not resolved by day 2 and does not rise to the level of a 
pausing or halting criterion (see sections 8.4.5 and 8.4.6). Day 2 dosing may be delayed for a 
maximum of 1 week. If the participant experiences other AEs (nonallergic in nature) on day 2 
that are expected from the vaccine based on data from the Phase 3 trials (e.g. fatigue, headache, 
fever, myalgia), then the second study vaccination may still be given on day 2 as scheduled. A 
participant may be moved to a general ward after the completion of their vaccinations and close 
monitoring, when safe to do so.
To assess potential effects of anxiety on the development of allergic reactions, and to support the 
psychological well-being of participants, each participant will complete standardized 
questionnaires assessing history of anxiety and past and current mental health within 30 days 
prior to or at Day 0. In addition, participants will have a mental health interview via a telehealth 
appointment before Day 0/admission to review questionnaire results and be offered strategies to 

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help manage distress. Vaccine-related anxiety will also be assessed at each timepoint, including 
before and after vaccine administration on Days 1 and 2. Responses will be assessed by a 
clinician, and a psychiatric evaluation and/or counseling or strategies to help with anxiety will be 
provided if indicated.
A member of the study team will perform videoconference, phone, and/or email follow-up with 
all participants within one week post-discharge to assess for any AEs from the study 
intervention. Participants will return to the NIH for follow-up visits approximately 1 and 5 
months post-discharge to provide additional research samples, including samples to assess their 
response to the vaccine. At one of the follow-up visits (per investigator discretion), participants 
will undergo allergy skin testing to investigate the potential role of IgE in triggering allergic 
reactions to the vaccine. Mental health/anxiety questionnaires will be readministered at 
approximately day 30 and month 5, and anxiety levels will be assessed at each follow-up visit. 
Clinical follow-up will be provided as needed. At month 5, a brief questionnaire to garner 
participant feedback on the perceived benefits and burdens of the mental health assessments 
conducted on this study will also be administered. At the 5-month follow-up visit, we will offer 
participants the opportunity to receive a booster dose of the Pfizer-BioNTech vaccine if they did 
not have a severe allergic reaction when they received the second dose in the ICU (ie, those who 
had CoFAR grade 2 reaction or less will be eligible for the booster). For participants who decline 
the booster vaccination, the 5-month visit will be the final study visit. 
All participants who opt in to receiving the booster dose at the 5-month visit will receive active 
vaccine; no placebo will be given. If the bivalent formulation (Original and Omicron 
BA.4/BA.5) of the vaccine is available at the NIH, participants will be given the option of 
receiving the bivalent or monovalent version as the booster dose; if the bivalent version is not 
available, the monovalent will still be offered. A consent addendum will be discussed with the 
participants about this choice. (Note: As of September 15, 2022, only 2 participants have yet to 
complete the 5-month visit, and it is unclear whether the NIH will have the bivalent version 
available for these 2 remaining visits.) A single IV line will be inserted prior to booster 
administration to allow for serial blood draws and rapid administration of fluids/medications if 
needed in the event of a reaction. The booster vaccine will be administered in an outpatient 
clinic, and medications necessary to treat an allergic reaction, including epinephrine, will be 
readily available. Participants will be observed in the clinic for at least 2 hours after the booster 
dose is administered. Vital signs will be checked at baseline and prior to discharge, and as 
indicated in case of development of symptoms, and we will draw blood pre-dose, 35 minutes 
post-dose, and 2 hours post-dose to assess for changes in biomarkers. A urinary specimen will be 
obtained pre-dose and the first void post-dose prior to discharge will be collected (if possible), to 
detect urinary biomarkers changes. A member of the study team will perform videoconference, 
phone, and/or email follow-up with participants who receive the booster vaccination within one 
week post-dose to assess for any AEs. Participants who received the booster dose will attend a 
final study visit at month 6 to undergo research procedures, including blood sample collection, to 
assess their response to the vaccine, and anxiety levels will be assessed. Clinical follow-up will 
be provided as needed. Information collected from participants receiving booster administration 
may provide additional reassurance that patients with a history of severe systemic allergic 
reactions to the first dose of the vaccine can safely receive a second dose and booster doses in an 

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outpatient setting, which is likely to be of significant public health interest. Unblinding will 
occur after the last participant has completed Visit 1.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The study population was chosen as they are unable to receive the recommended number of 
doses of the COVID-19 mRNA vaccines based on current FDA and CDC guidelines, and 
therefore information regarding the safety of administering a second dose (whether the same 
vaccine or a discordant vaccine) to this population is critically needed. They are also a group that 
has had a convincing allergic reaction to the initial dose of the vaccine, and therefore are likely to 
inform the mechanism of these reactions if they experience a reaction upon challenge with a 
subsequent dose of the Pfizer-BioNTech vaccine. Based on data reported to VAERS, the rate of 
allergic reactions to these vaccines is significantly more prevalent in women, and therefore we 
anticipate that our study population will be skewed towards a predominance of female 
participants. We will make every effort to ensure that any reactions that are observed can be tied 
to the active vaccine, and therefore are excluding participants who have received any allergen 
immunotherapy within the 24 hours prior to challenge or after the vaccination, or other 
vaccination within 14 days. We are including placebo controls as false positive reactions are not 
uncommonly observed in drug and other allergen challenges, as anxiety can lead to symptoms 
that clinically mimic anaphylaxis. We hope to begin to understand the mechanisms of allergic 
reactions to the vaccines, and so have excluded medication use that would be expected to 
interfere with analysis in mechanistic studies. This includes medications such as 
immunomodulators including systemic steroids, biologics including T helper 2 (Th2) cytokine 
(e.g. IL-4, IL-5, IL-13) inhibitors, as well as others such as rituximab and the 5-lipoxygenase 
inhibitor zileuton. Because of the risk that participants will experience an allergic reaction that 
may be severe, we are excluding pregnant women from enrolling.
4.3
JUSTIFICATION FOR DOSE
Administration and dosing for the Pfizer-BioNTech vaccine will be in accordance with the FDA-
approved dose as detailed in the prescribing information.
5
STUDY POPULATION
5.1
INCLUSION CRITERIA
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria:
1. Ability to provide informed consent.
2. Stated willingness to comply with all study procedures (including discontinuing 
medications as needed [section 5.5]) and availability for the duration of the study. 
3. Aged 16-69 years.
4. Must have experienced a systemic allergic reaction (CoFAR Grade 2 or 3 reaction 
regardless of tryptase OR Grade 1 reaction with elevated tryptase [1.2 X baseline plus 2 
ng/mL] per modified CoFAR Grading Scale for Systemic Allergic Reactions Version 3.0) 
to the first dose of the Pfizer-BioNTech or Moderna COVID-19 vaccine. Patients without 
documented hypoxia, hypotension, or evidence of end-organ damage who were treated 
with epinephrine infusion would be considered as CoFAR Grade 3 reaction and may 
be eligible per investigator discretion.

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5. Must be at least 28 days out from their first dose of the Moderna vaccine or 21 days from 
their first dose of the Pfizer-BioNTech vaccine before proceeding with the placebo or 
vaccine challenge in this study.
6. Have a primary care physician or other health care provider who will manage their 
medical care outside of this study.
5.2
EXCLUSION CRITERIA
An individual who meets any of the following criteria will be excluded from participation in this 
study:
1. Experienced a Grade 4 systemic allergic reaction (per CoFAR Grading Scale for 
Systemic Allergic Reactions Version 3.0) to the first dose of the Pfizer-BioNTech or 
Moderna COVID-19 vaccine.
2. Known exposure to SARS-CoV-2 and still within the quarantine window.
3. Symptoms consistent with acute COVID-19 infection or known COVID-19 infection 
(positive reverse transcription-polymerase chain reaction [RT-PCR] or antigen test) and 
still within the quarantine window
4. Have an acute illness, including body temperature greater than 100.4 degrees F, within 14 
days prior to enrollment.
5. History of autoimmune or other disorders requiring systemic immune modulators.
6. Are moderately or severely immunocompromised.
7. History of acute urticaria within 28 days prior to enrollment.
8. Pregnant.
9. Have received any vaccines within 14 days prior to enrollment.
10. Scheduled or planned receipt of approved or experimental vaccine prior to visit 3.
11. Had any allergen immunotherapy administration within 24 hours prior to the first study 
vaccination or plan to receive within 24 hours after the second study vaccination.
12. Have received a biological therapy within 6 months prior to enrollment.
13. Use of systemic steroids for any reason within 28 days prior to enrollment.
14. Use of zileuton within 14 days prior to enrollment.
15. Use of EUA monoclonal antibodies casirivimab and indevimab, or bamlanivimab, or any 
other antibody agent for treatment or prevention of COVID-19 within 3 months of 
randomization.
16. Presence of condition(s) that, in the judgment of the investigator or the referring 
physician, may put the participant at undue risk or make them unsuitable for participation 
in the study.
5.2.1
Exclusion of Special Populations
Children, adults who lack capacity to consent, and pregnant women: We are able to obtain 
knowledge about allergic responses to the mRNA COVID-19 vaccines without exposing 
children under age 16 (even though the Pfizer-BioNTech vaccine is authorized for emergency 
use in individuals 5 to 15 years of age, and authorizations for lower ages are anticipated), adults 
who lack capacity to consent, and pregnant women to the potential risk of severe allergic 
reactions.

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5.3
INCLUSION OF VULNERABLE PARTICIPANTS
5.3.1
Participation of Children
Currently, the Pfizer-BioNTech vaccine is the only vaccine approved for use in children 16 to 17 
years of age. They have no options for seeking another type of vaccine for full vaccination 
(unlike adults who can receive a non-mRNA vaccine), so there is an urgent public health need to 
determine the safety of giving a second dose in this population in order for them to be fully 
protected against COVID-19. Furthermore, there is likely to be significant hesitancy for 
practicing allergists to give a second dose to children who have had an anaphylactic reaction to 
the first dose unless evidence can be generated to support that it is safe to do so.
5.3.2
Adult Subjects Who Lack Capacity to Consent to Research Participation
Individuals who are unable to provide initial informed consent are excluded from the study. If 
participants lose the ability to provide ongoing consent subsequent to giving initial consent, they 
will be withdrawn from the study.
5.3.3
Participation of NIH Staff or Family Members of Study Team Members
NIH staff and family members of study team members may be enrolled in this study as this 
population meets the study entry criteria. Neither participation nor refusal to participate as a 
subject in the research will have an effect, either beneficial or adverse, on the participant’s 
employment or position at NIH.
Every effort will be made to protect participant information, but such information may be 
available in medical records and may be available to authorized users outside of the study team 
in both an identifiable an unidentifiable manner.
The NIH investigator will provide and request that the NIH staff member review the Frequently 
Asked Questions (FAQs) for Staff Who are Considering Participation in NIH Research and the 
Leave Policy for NIH Employees Participating in NIH Medical Research Studies (NIH Policy 
Manual 2300-630-3). Please see section 10.1.3 for consent of NIH staff.
5.4
INCLUSION OF PREGNANT WOMEN, FETUSES OR NEONATES
Not applicable
5.5
LIFESTYLE CONSIDERATIONS
During this study, participants are asked to:

Discontinue any medication (e.g., oral antihistamines) that might interfere with the 
vaccine challenge procedure, skin testing, or booster administration (as applicable) within 
an appropriate timeframe prior to the target procedure, depending on the medication.

Refrain from taking multivitamins or supplements containing biotin (vitamin B7, which 
is commonly found in hair, skin, and nail supplements and multivitamins) for 12 hours 
before Visits 1, 3, 4, and 6.
5.6
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
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participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE).
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
modifiable factor may be rescreened. Rescreened participants should be assigned the same 
participant number as for the initial screening.
5.7
STRATEGIES FOR RECRUITMENT AND RETENTION
Participants will be recruited from referrals from outside physicians and from investigators or 
employees in the NIH Clinical Center. Letters and/or emails may be sent to physicians, 
allergists/immunologists, and other specialists, as well as directly to potential participants for 
subject recruitment. Fliers and other written information may be posted on the NIH campus, in 
newspapers and on news sites, and in public spaces including, but not limited to, libraries, 
listservs, and community events, advertising the study. Foundations and other patient advocacy 
groups may be contacted. The NIH media office may be contacted to issue a press release 
regarding the study. The study will be listed on clinicaltrials.gov. Information about the study 
may also be placed on social media sites.
5.7.1
Costs
No cost to participants is expected.
5.7.2
Compensation
Participant travel will be paid directly or reimbursed, per NIAID policy. However, participants 
will also be reimbursed for travel for their first in-person visit to the NIH (which would typically 
not be reimbursed per policy).
Participants will be compensated for study events and procedures after screening as summarized 
below:
Inpatient stay Day 0: $350
Inpatient stay Day 1: $350
Inpatient stay Day 2: $350
Inpatient stay Day 3: $300
Additional stay in ICU (e.g., if longer stay is needed to treat allergic reaction/AE): $300/day
Additional stay on ward (e.g., if longer stay is needed to treat allergic reaction/AE): $250/day
Blood draw (completion of all required per study team for study visit 1): $150
Nasal swab: $25
Urine collection (completion of all required for study visit 1): $25
Outpatient follow-up visit: $200
Outpatient blood draw: $50 ($150 at visit 4 only for participants who receive booster 
vaccination)
Outpatient skin testing: $75

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Visits 2 and 5 (as applicable) phone call/videoconference: $20 each
Mental health/anxiety questionnaires: $10 for each timepoint. Questionnaires completed during 
screening/enrollment and visit 1 (day 0) will be compensated $10 total at the completion of visit 
1. Participants must complete all questionnaires for the corresponding timepoint to receive the 
questionnaire compensation for that timepoint.
Psychiatric consultation (via telehealth appointment): $20
The total maximum compensation for the required study visits and procedures as scheduled is 
$2,195; however, compensation may be more than this if the participant receives a booster 
vaccination or if additional inpatient days or additional procedures are required. Screening 
procedures are not compensated. Subjects will receive remuneration after visit 2 (for visits 1 and 
2) and after visit 4 or 6 (for visits 3, 4, 5, and 6, as applicable).
6
STUDY INTERVENTIONS
6.1
STUDY INTERVENTIONS ADMINISTRATION
6.1.1
Study Intervention Description 
The Pfizer-BioNTech monovalent COVID-19 vaccine (Comirnaty) is approved by the FDA in 
individuals 12 years of age and older for active immunization to prevent COVID-19 caused by 
SARS-CoV-2. It is also authorized for use under EUA in additional populations, as described 
above (section 2.2). The bivalent formulation (Original and Omicron BA.4/BA.5) is authorized 
for use under EUA as a single booster dose for individuals 12 years of age and older who are at 
least 2 months removed from the completion of their completed primary vaccination or have 
received the most recent booster dose with any authorized or approved monovalent COVID-19 
vaccine. The active ingredient in both formulations is nucleoside-modified mRNA encoding the 
SARS-CoV-2 spike protein. Additional details regarding the vaccine are provided below and in 
the prescribing information documents.[28, 29]
Commercially available sterile, preservative-free 0.9% Sodium Chloride Injection, USP will be 
used as placebo.
6.1.2
Dosing and Administration
A single dose of the Pfizer-BioNTech vaccines is 0.3 mL. Each dose of the placebo vaccine will 
match this volume (0.3 mL). All study vaccines will be administered intramuscularly in the 
deltoid in the order determined by the randomization schedule; the first and second vaccinations 
will be in opposite arms.
6.1.3
Booster Vaccination
Participants who receive a booster vaccination at visit 4 will receive a standard dose of the 
monovalent or bivalent Pfizer-BioNTech vaccine according to availability and participant 
choice.

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6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1
Acquisition and Accountability
The study drug will be distributed and accounted for by the NIH pharmacy according to standard 
pharmacy procedures.
6.2.2
Formulation, Appearance, Packaging, and Labeling
The Pfizer-BioNTech COVID-19 vaccines are supplied as frozen suspensions in vials with gray 
caps and labels with gray borders, and are not diluted prior to use. The label on the vials of the 
bivalent formulations are marked with the word “Bivalent.” Each dose contains 30 mcg of a 
modified messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of SARS-CoV-2. 
Each dose of the Pfizer-BioNTech COVID-19 vaccines also includes the following ingredients: 
lipids (0.43 mg ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.05 mg 
2-[PEG-2000]-N,N-ditetradecylacetamide, 0.09 mg 1,2-distearoyl-sn-glycero-3-phosphocholine, 
and 0.19 mg cholesterol), 0.06 mg tromethamine, 0.4 mg tromethamine hydrochloride, and 31 
mg sucrose. The Pfizer-BioNTech COVID-19 vaccines do not contain preservative. The vial 
stoppers are not made with natural rubber latex.
The Pfizer-BioNTech vaccines will be labeled per pharmacy procedures and in accordance with 
regulatory requirements.
Each mL of placebo vaccine contains sodium chloride 9 mg and water for injection, quantity 
sufficient. It contains no bacteriostat, antimicrobial agent, or added buffer. The solution may 
contain hydrochloric acid and/or sodium hydroxide for pH adjustment.  
6.2.3
Product Storage and Stability
Pfizer-BioNTech COVID-19 vaccine will be supplied in cartons in thermal containers with dry 
ice. Once received, the vial cartons may be stored in an ultra-low temperature freezer between -
90ºC to -60ºC (-130ºF to -76ºF) or immediately transferred to the refrigerator [2ºC to 8ºC (35ºF 
to 46ºF)], thawed, and stored for up to 10 weeks. The 10-week refrigerated expiry date should be 
recorded on the carton at the time of transfer. Once vials are thawed, they should not be refrozen. 
If cartons are received at 2°C to 8°C, they should be stored at 2°C to 8°C. The carton should be 
checked to ensure it has been updated to reflect the 10-week refrigerated expiry date. During 
storage, minimize exposure to room light, and avoid exposure to direct sunlight and ultraviolet 
light. 
If not previously thawed at 2ºC to 8ºC (35ºF to 46ºF), vials should be thawed at room 
temperature [up to 25ºC (77ºF)] for 30 minutes prior to use. Vials may be stored at room 
temperature [8°C to 25°C (46°F to 77°F)] for a total of 12 hours prior to the first puncture. After 
first puncture, the vial should be held between 2ºC to 25°C (35°F to 77°F). Vials should be 
discarded 12 hours after first puncture. 
Placebo should be stored at 20° C to 25°C (68° F to 77° F).
6.2.4
Preparation
The Pfizer-BioNTech COVID-19 vaccines are supplied as a frozen suspension that does not 
contain preservative. Each vial must be thawed prior to administration, and must not be diluted. 

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Detailed preparation instructions are provided in the full prescribing information documents.[28, 
29]
The placebo vaccine will be prepared according to standard pharmacy procedures.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING
Participants will be randomized to receive either Pfizer-BioNTech vaccine or placebo on Day 
1 in a 1:1 ratio at enrollment via block randomization. On Day 2, subjects will receive whichever 
of vaccine or placebo that was not given on Day 1. A randomization scheme will be generated by 
the NIAID Biostatistics Research Branch who will provide a randomized list of arm assignments 
to the NIH Clinical Center Pharmacy. The randomization code list will be maintained by the 
Investigational Drug Control Unit (IDCU) in the electronic Investigational Drug Management 
System (IDMS).
The participants, the clinical staff, and the study team will be blinded to the order of study 
vaccine assignments. The unblinded pharmacy staff is responsible for maintaining security of the 
assignments. 
Intentional unblinding: Unblinding will occur after the last participant has completed Visit 1. 
There will be no emergency unblinding for CoFAR Grade 3 or lower reactions because allergic 
and anaphylactic reactions to the vaccine are expected and will be treated per standard clinical 
care, and it is not necessary to unblind to do so. However, if a CoFAR Grade 4 or higher 
systemic allergic reaction or other life-threatening AE occurs, then both the investigator and the 
participant will be unblinded. If a CoFAR Grade 4 or higher reaction occurs on day 1, then the 
participant will not receive the study intervention the next day (either placebo or vaccine). 
To break a treatment blind, the principal investigator will request a participant’s treatment 
assignment from the IDCU. If an emergency request for treatment assignment is made by an 
individual other than the principal investigator and the principal investigator is not immediately 
available, the request will be made to one of the physician associate investigators, who will then 
contact the IDCU or appropriate NIH pharmacy after-hours contact to obtain the treatment 
assignment. If a participant’s study agent assignment is unblinded, the information will be 
provided to only the individuals needing it for treatment decisions; all attempts will be made to 
maintain the blind of the study team.
Unintentional unblinding: If the blind is unintentionally broken during the challenge, the study 
will proceed as normal, and the principal investigator will create a plan for preventing the 
recurrence of a similar incident, as appropriate. Since the active vaccine is known to have 
adverse side effects (e.g. fatigue, headache, fever, etc) based on data from the Phase 3 trials, 
patients who experience these symptoms may be unintentionally unblinded. However, if the 
participant experiences these symptoms on Day 2 (e.g. after receiving vaccine on Day 1), they 
may still receive the study vaccine on Day 2 without intentionally breaking the blind. Although 
these symptoms may indicate the participant received the active vaccine, this cannot be 
absolutely confirmed without direct knowledge of the participant’s assignment; therefore, these 
instances will be evaluated by the principal investigator (without purposefully breaking the blind 
unless necessary) and will only be reported as outlined below if the assignment has been 
definitively revealed.

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Intentional and unintentional unscheduled unblinding will be documented in the appropriate 
source and/or research record and will include the reason for the unscheduled unblinding, the 
date it occurred, who approved the unblinding, who was unblinded, who was notified of the 
unblinding, and the plan for the participant. The principal investigator will report all cases of 
intentional and unintentional unscheduled unblinding to the data and safety monitoring board 
(DSMB) in writing within 1 business day after site awareness via email to the DSMB mailbox 
(niaiddsmbia@niaid.nih.gov) outlining the reason for the unblinding and the date it occurred. 
The report will also be submitted to the sponsor medical monitor. If the unblinding meets the 
definition of a reportable event, it will be reported to the IRB according to NIH Human Research 
Protections Program (HRPP) Policy 801.
If an SAE has resulted in unblinding, this information will be included in the SAE report.
6.4
STUDY INTERVENTION COMPLIANCE
Participants in this study will receive the full dose of the assigned vaccine/placebo under direct 
observation.  
6.5
CONCOMITANT THERAPY
The following medications are prohibited during participation in the study: 
•
Systemic immunomodulators including systemic steroids. 
•
Biologic agents that will interfere with the study objectives at the discretion of the 
investigator. 
•
EUA monoclonal antibodies casirivimab and indevimab, or bamlanivimab, or any 
COVID-19-specific biologic including antibodies or immunomodulator for at least 5 half-
lives. 
•
Zileuton. 
•
Any investigational or approved vaccines administered outside of the study prior to visit 
3 and, for participants receiving a booster vaccination at visit 4, at least 2 months before 
visit 4 through visit 6. 
•
Any allergen immunotherapy administration within 24 hours prior to the first study 
vaccination through 24 hours after the second study vaccination, and from 24 hours prior 
to through 24 hours after visit 4 (for participants receiving the booster vaccination).
Since one of the goals of this study is to understand the mechanisms of allergic reactions to the 
COVID-19 vaccines, these medications have been excluded since they may interfere with 
analysis in mechanistic studies. 
Participants may be asked to discontinue use of antihistamines and drugs with antihistamine 
properties prior to the study intervention as well as prior to skin testing at visit 3 or 4 and booster 
vaccination at Visit 4 (as applicable) since these medications can mask signs and symptoms of an 
allergic reaction, thereby reducing the accuracy of skin testing and affecting results of research 
tests following the booster vaccination. Participants will be asked to discontinue these 
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intervention.[31] These medications can be resumed once the participant is discharged at the end 
of Visit 1 and after Visit 3 or 4. 
Unless medically contraindicated, participants may also be asked to discontinue use of beta 
blockers, ACE inhibitors, and NSAIDS that are thought to interfere with treatment of allergic 
reactions or that may act as eliciting factors that increase reactivity in susceptible individuals[31] 
for a time period of 5 half-lives of the medication prior to the vaccine challenge at Visit 1 and the 
booster vaccination at Visit 4 (as applicable). They can resume these medications once they 
complete the study interventions at the respective visit.
7
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1
DISCONTINUATION OF STUDY INTERVENTION
Study intervention may be discontinued for an individual participant (i.e., pausing), or it may be 
discontinued for all participants and enrollment suspended (i.e., halting). Pausing and halting 
rules and procedures are described in sections 8.4.5 and 8.4.6.
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY
Participants are free to withdraw from participation in the study at any time upon request. 
Criteria and procedures for withdrawal and replacement of a participant by the investigator are 
provided in section 8.4.3.
7.3
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if he or she fails to respond to the 1 week post-
discharge phone and/or email contact. Study site staff will make at least 3 attempts to contact 
participants to complete this follow-up visit. These contact attempts should be documented in the 
participant’s medical record or study file. Should the participant continue to be unreachable, they 
will be considered to have withdrawn from the study with a primary reason of lost to follow-up.
8
STUDY ASSESSMENTS AND PROCEDURES
The following study assessments and procedures will be performed according to the schedule 
provided in section 1.3.
8.1
SCREENING PROCEDURES
8.1.1
Screening Activities Performed Prior to Obtaining Informed Consent
Potential study participants may be identified by medical chart review, from referrals, or from a 
response to a study advertisement, and initially contacted by a member of the study team in 
person, by videoconference, over the phone, or by email. During this initial contact, the potential 
participant will be provided information on the study and asked to provide verbal permission for 
screening. If a participant provides verbal permission for screening, they may be screened 
remotely via an NIH-approved videoconferencing platform/by phone/by email. Medical records, 
including imaging and laboratory studies, may be requested and reviewed by the study team, 
demographic information will be collected, and concomitant medications will be reviewed. 
Participants will be asked about their reaction to the first dose of the COVID-19 vaccine as well 
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(if present) that may increase their risk of having a severe allergic reaction. Screened individuals 
who are found to be eligible or potentially eligible for enrollment and are interested in 
participating in the study will be scheduled for a Visit 1 at the study site. Individuals may be 
consented to the protocol up to Day -60 by phone/videoconference or in-person at Visit 1. In 
some cases, individuals with comorbidities that may increase study risks may be asked to come 
to the NIH Clinical Center for additional screening (see section 8.1.2).
8.1.2
Screening Activities Performed After a Consent for Screening Has Been Signed
Individuals with comorbidities identified at initial screening that may place them at higher risk 
for having a severe allergic reaction will be asked to come to the NIH for additional screening 
procedures (e.g., pulmonary function testing, chest X-ray, ECG, echocardiogram, flexible 
nasolaryngoscopy, and blood laboratory testing) to ensure the individual is stable to undergo the 
study intervention. Written informed consent to participate in this study will be obtained (either 
by phone or in person) before any of these additional screening procedures are performed. 
Individuals who are found not to be eligible to undergo the study intervention after these 
screening tests will be considered screen failures.
Screening procedures must be completed within 30 days prior to Day 1. Eligibility will be 
confirmed at Day 0 after pregnancy test (if applicable) and SARS-CoV-2 test results are known.
8.2
EFFICACY ASSESSMENTS
8.2.1
Clinical Evaluations
Demographics: Basic demographic information will be collected.
Medical and medication history/concomitant medication review: At screening (see above), 
we will review NIH and off-site medical records, as applicable, and interview participants to 
collect information about conditions or medications that may impact study eligibility or risk of 
developing severe allergic reactions to the study vaccinations. After enrollment, reviews will 
focus on updates since the last assessment, with a particular focus on new symptoms and AEs.
Targeted physical exam: Targeted physical exams will be conducted by a study physician or 
other qualified medical professional prior to each study vaccination and at other timepoint(s) as 
needed to assess new symptoms or AEs. A targeted physical exam may be conducted at 
screening for individuals asked to come to the NIH for additional screening procedures to assess 
the status of comorbid conditions.
Vital signs: Temperature, pulse rate, respiratory rate, oxygen saturation, and blood pressure will 
be measured within 30 minutes prior to each study vaccination, at the time of blood draws, and 
as clinically indicated after each study vaccination during Visit 1. At Visit 4, for participants who 
receive the booster dose, vital signs will be checked at baseline and prior to discharge, and as 
indicated in case of development of symptoms of an allergic reaction; otherwise, vital signs will 
be obtained per clinical routine at Visits 3, 4, and 6. Vital signs may be measured at screening for 
individuals asked to come to the NIH for additional screening procedures to assess the status of 
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Height and weight: Growth parameters (height and weight) will be measured prior to the first 
study vaccination.
Peak flow measurement and impulse oscillometry: Peak expiratory flow and respiratory 
resistance of the lungs will be measured by standard methods prior to each study vaccination on 
days 1 and 2. May be repeated during Visit 1 or at follow-up visits at investigator discretion.
Nasal swab: A nasal swab (mid-turbinate or nasopharyngeal per current Clinical Center 
practice) will be collected by standard methods prior to the first study vaccination for SARS-
CoV-2 testing by PCR. If the SARS-CoV-2 result is positive, Visit 1 will be delayed until the 
participant has recovered and is outside of the quarantine window.
Pregnancy test: Serum pregnancy testing will be performed for participants of childbearing 
potential. The result must be confirmed negative prior to proceeding with the study vaccination 
(at Visit 1) and booster dose (as applicable at Visit 4).
Skin testing: Skin allergy testing to the vaccine, PEG-polysorbate 80-containing medications, 
and/or other allergens will be conducted according to practice parameters and recent 
guidelines[32, 33]. In general, all participants will undergo skin prick testing at Visit 3 or Visit 4. 
If skin prick testing is negative, intradermal allergen testing will be performed. However, the 
type and nature of the skin testing performed may change in accordance with standard practice, 
as guidelines are continually updated.
Urine collection: One void prior to each study vaccination and an additional void(s) after each 
study vaccination and/or the onset of an allergic reaction will be collected using standard 
methods at Visit 1. At Visit 4 (participants who opt in to booster dose only), one void prior to the 
booster dose and the first void post-dose will be collected, if possible. Urine samples will be used 
for laboratory testing (section 8.2.2) and storage.
IV insertion: Two peripheral IV lines will be inserted for Visit 1 by qualified personnel using 
standard methods to allow for frequent blood draws and rapid administration of 
fluids/medications if needed in the event of a reaction. For participants receiving a booster 
vaccination at Visit 4, a single IV line will be inserted prior to booster administration to allow for 
serial blood draws and rapid administration of fluids/medications if needed in the event of a 
reaction.  
Blood collection: Blood samples will be collected from an IV line when possible, or via 
venipuncture using standard methods, for laboratory testing (section 8.2.2) and storage. During 
visit 1, samples will be collected before each study vaccination and approximately 35 minutes 
(+/-15 minutes), 2 hours (+/-30 minutes), 6 hours (+/-30 minutes), and 24 hours (+/-1 hour) after 
each study vaccination. The 24-hour blood draw for day 1 will also serve as the baseline blood 
draw for day 2. An additional blood draw will occur on day 3 of visit 1 prior to discharge. 
Approximately 464.5 mL of blood will be obtained at visit 1. Approximately 71 mL will be 
obtained at visit 3, at visit 4, and at visit 6; for participants who opt in to the booster vaccination 
at Visit 4, the total volume for that visit will be 245 mL. Additionally, up to 150 mL of blood 
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study-related concern); however, blood collection would be restricted to only clinically indicated 
laboratory assessments if the maximum blood volume allowed for research purposes has been 
reached. Weight-based adjustments to blood volumes collected for research testing will be made 
as needed for minor participants to remain within the limits allowed at the CC.
Clinical photography: If a participant develops a skin rash after receiving a study vaccination, 
photographs of the affected area(s) may be taken with the participant’s permission. Identifiable 
photographs will be kept in a secure database and will not be released without the permission of 
the study participant. Participants will sign the standard NIH photography consent form before 
photographs are taken.
Anxiety/mental health assessments: The following standardized questionnaires assessing past 
and current mental health and anxiety will be completed by the participant through the research 
electronic data capture (REDCap) system (on an electronic device during an in-person visit or by 
accessing a link sent by email) or on paper:

Mental health history questionnaire

Impact of Events Scale-6

State-Trait Anxiety Inventory

Generalized Anxiety Disorder-7 scale

Patient Health Questionnaire-9

World Health Organization Disability Assessment Schedule-2
Only participants who speak English or Spanish will complete these questionnaires, as these are 
the only languages in which they are available. 
All participants will be asked to rate their current level of anxiety based on a 10-point scale at 
several different timepoints during the study. 
Mental health questionnaire results will be reviewed and relaxation strategies and other 
recommendations will be provided by a National Institute of Mental Health mental health 
clinician via a brief telehealth appointment (prior to admission). Subsequent sessions will be 
scheduled as needed based on ongoing reviews of mental health/anxiety assessments. 
Participants may be given informational materials to help manage stress.
A brief questionnaire to garner participant feedback on the perceived benefits and burdens of the 
mental health assessments conducted on this study will be administered at month 5.
Pulmonary function testing: Pulmonary function tests will be performed using standard 
methods at screening, only for individuals with comorbidities that increase their risk of 
developing a severe allergic reaction to the study vaccination(s).
Chest X-ray: Chest X-ray will be performed using standard methods at screening, only for 
individuals with comorbidities that increase their risk of developing a severe allergic reaction to 
the study vaccination(s).

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ECG: ECG will be performed using standard methods at screening, only for individuals with 
comorbidities that increase their risk of developing a severe allergic reaction to the study 
vaccination(s).
Echocardiogram: Echocardiogram will be performed using standard methods at screening, only 
for individuals with comorbidities that increase their risk of developing a severe allergic reaction 
to the study vaccination(s).
Flexible nasolaryngoscopy: Flexible nasolaryngoscopy will be performed using standard 
methods to allow assessment of the airway at screening, only if there is concern that a participant 
may have a difficult airway (e.g., due to history of laryngeal trauma, neck/thyroid surgery, etc).
8.2.2
Biospecimen Evaluations
Specimens (blood, urine, and nasal swabs) will be used to assess: 
•
Overall atopic status 
•
Pre-existing antibodies to polyethylene glycols (Sample analysis will not be completed 
prior to vaccination; therefore, results will not be used to assess eligibility.) 
•
Known mediators of systemic reactions due to mast cell activation (e.g., serum tryptase 
and urinary leukotrienes, prostaglandins, histamine) 
•
General markers of an acute inflammatory response (e.g., serum IL-6) 
•
Activation of the classical and alternative complement pathways 
•
Contact activation of the kinin system 
•
Activation of basophils and neutrophils
•
Unsupervised proteomics, metabolomics, and whole blood transcriptomics 
•
Analysis of peripheral blood mononuclear cells (PBMCs) may also be explored to assess 
for new mechanisms 
•
Evidence of clonal mast cell disease and genetic variants that may increase the risk and/or 
severity of allergic reactions (e.g. hereditary alpha tryptasemia, clonal mast cell disease)
•
Autoantibodies pre and post COVID-19 vaccination
Specific laboratory studies may include those listed below. Assays may be removed or added 
based on the number and character of reactions seen within the trial. In addition, the timepoints 
for the conduct of specific laboratory studies may change from what is specified below. 
Specimens will be processed at the Laboratory of Allergic Diseases (LAD), Laboratory of Viral 
Diseases (LVD), Laboratory of Immune System Biology (LISB), and the Laboratory of 
Bacteriology at the Rocky Mountain Laboratories at NIAID, the Department of Laboratory 
Medicine (DLM) at NIH (including send-outs to Mayo Clinic), and the Systemic Autoimmunity 
Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Coded 
specimens will also be sent to collaborators at Yale University, Virginia Commonwealth 
University, Stanford University, University of North Carolina, University of Pittsburgh, KalVista 
Pharmaceuticals, Inc., and the US FDA for processing.

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Blood/serum/plasma:
The following tests may be performed for all participants:
•
Whole blood for genetic analysis of the tryptase locus, c-kit locus, and other genetic 
variants that might influence the risk and/or severity of allergic reactions (Visit 1, pre-
dosing) 
•
Total IgE (Visit 1, pre-dosing Day 1 only) 
•
Allergen-specific IgE (Visit 1, pre-dosing) 
•
Anti-Polyethylene glycol (PEG) IgE, IgG, and IgM antibody measurements (Visit 1, pre-
dosing, and Visits 3, 4, and 6) 
•
Anti-SARS-CoV-2 antibodies and functional antibodies (Visit 1, pre-dosing, and Visits 3, 
4, and 6) 
•
Serum total and mature tryptase (Visit 1, pre-dosing, and post-dosing (placebo and 
vaccine) at 35 minutes and 2 hours) 
•
Complement activation testing (Visit 1, pre-dosing, and post-dosing (placebo and 
vaccine) at 35 minutes and 2 hours)
•
Flow cytometry for immunophenotyping and assessment of immune activation (Visit 1, 
pre-dosing, and post-dosing (placebo and vaccine) at 35 minutes, 2 hours, 6 hours, and 24 
hours; and Visits 3, 4, and 6) 
•
Flow cytometry and other assays to assess basophil and neutrophil activation (Visit 1, 
pre-dosing, and post-dosing (placebo and vaccine) at 35 minutes and 2 hours)
•
CBC with differential (Visit 1, pre-dosing, and post-dosing (placebo and vaccine) at 35 
minutes, 2 hours, 6 hours, and 24 hours; and Visits 3, 4, and 6) 
•
Whole blood and single cell transcriptomics and/or CITE-seq (Visit 1, pre-dosing, and 
post-dosing (placebo and vaccine) at 35 minutes, 2 hours, 6 hours, and 24 hours; and 
Visits 3, 4, and 6) 
•
Plasma proteomics and metabolomics (Visit 1, pre-dosing, and post-dosing (placebo and 
vaccine) at 35 minutes, 2 hours, 6 hours, and 24 hours; and Visits 3, 4, and 6) 
•
PBMC separation and storage (Visit 1, pre-dosing, and post-dosing (placebo and vaccine) 
at 35 minutes, 2 hours, 6 hours, and 24 hours; and Visits 3, 4, and 6) 
•
Plasma Kallikrein (Visit 1, pre-dosing, and post-dosing (placebo and vaccine) at 35 
minutes and 2 hours) 
•
Measurement of platelet activating factor (PAF) and platelet activating factor 
acetylhydrolase (PAF-AH) as well as neutrophil nets (Visit 1, pre-dosing, and post-
dosing (placebo and vaccine) at 35 minutes and 2 hours) 
•
Serum cortisol level (Visit 1, pre-dosing, and post-dosing (placebo and vaccine) at 35 
minutes and 2 hours)
•
Metanephrine/normetanephrine (Visit 1, pre-dosing, and post-dosing (placebo and 
vaccine) at 35 minutes and 2 hours)
•
Autoantibody levels (Visit 1, pre-dosing; Visit 3, Visit 4, pre-dosing; and Visit 6)
•
Serum pregnancy test for participants of childbearing potential (Visit 1 prior to study 
intervention)

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For subjects who opt in to receiving the booster dose of vaccine at Visit 4, the following tests 
may be performed pre-dose, 35 minutes (+/-15 minutes) post-dose, and 2 hours (+/-30 minutes) 
post-dose. Assays may be removed or added based on the number and character of reactions seen 
within the trial. (Tests indicated for Visit 4 in the previous list will serve as the pre-dose 
assessment.)  

Serum total and mature tryptase 

CBC with differential 

Complement activation testing

Plasma Kallikrein 

Measurement of platelet activating factor (PAF) and platelet activating factor 
acetylhydrolase (PAF-AH) as well as neutrophil nets 

PBMC separation and storage

Flow cytometry for immunophenotyping and assessment of immune activation

Flow cytometry and other assays to assess basophil and neutrophil activation

Whole blood and single cell transcriptomics and/or CITE-seq 

Serum cortisol level

Metanephrine/normetanephrine

Serum pregnancy test for participants of childbearing potential (prior to booster 
vaccination)
Urine:
The following may be performed for all participants:
•
Urinary LTE4, N-methyl histamine (NMH), Prostaglandin D2, and 2,3-Dinor-11Beta-
Prostaglandin F2 Alpha (Visit 1, pre-dosing and first void(s) following vaccine 
administration and/or onset of reaction; Visit 4 (participants who opt in to booster dose 
only), pre-dose and first void post-dose prior to discharge, if possible) 
Nasal swab:
The following will be performed for all participants:
•
SARS-CoV-2 virus testing by RT-PCR using nasal swab (Visit 1 prior to study 
intervention)
8.2.3
Samples for Genetic/Genomic Analysis
8.2.3.1
Description of the scope of genetic/genomic analysis
Blood, plasma/serum, and/or urine may be used for:

transcriptomic, proteomic, and metabolomic analyses to explore innate and adaptive 
immune cell activation, function, and metabolism

genetic analysis of the tryptase locus and other genetic variants that might influence the 
risk and/or severity of allergic reactions

D816V mutation testing as an indicator of clonal mast cell disease

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Whole genome sequencing will not be performed under this study, but we will refer interested 
participants to the NIAID Central Sequencing Protocol (17-I-0122) for genomic sequencing. If a 
participant chooses to co-enroll on this protocol and 17-I-0122, we will have access to the 
identified findings from whole genome/exome sequencing via the Genomic Research 
Information System platform for use in this study to further inform our analyses. The informed 
consent document for 17-I-0122 describes the accessibility of the data generated to NIH 
researchers, and no additional samples outside of those required of each protocol will be 
obtained.
8.2.3.2
Description of how privacy and confidentiality of medical 
information/biological specimens will be maximized
Each participant will be assigned a unique identification number, and these numbers rather than 
names or other personally identifiable information will be used to collect, store, and report 
participant information. All biospecimens will be labeled with unique identification numbers. 
Only investigators or their designees will have access to the specimens and data. See section 10.3 
for additional details regarding confidentiality and privacy protections.
8.2.3.3
Management of Results
Analyses under this protocol may identify results or incidental findings that are relevant to the 
health or medical care of participants. In general, a result would only be returned if the test is run 
in DLM or if confirmatory testing in a laboratory certified by the Clinical Laboratory 
Improvement Amendments (CLIA) is available. If needed, the study team will contact the 
participant and request a sample for confirmatory testing. After confirmation, the principal 
investigator or designee will contact the subject to inform them of the finding and counsel them 
on the result. The study team may also provide consultation with a participant’s healthcare 
provider based on the result. Many research laboratory tests are not CLIA-certified, so generated 
data cannot be meaningfully interpreted outside the narrow focus of the study and will not be 
routinely returned to participants or their physicians. However, it is possible that the principal 
investigator may determine a result to be important to the participant’s health even if a 
CLIA-certified test is not available or feasible; in this case, the result would be returned. 
8.2.3.4
Genetic counseling
If a genetic analysis performed on this study generates an individually relevant finding that 
would be returned to a participant, the principal investigator will provide counseling or refer the 
participant for genetic counseling through the NIH at no cost.
8.3
 SAFETY AND OTHER ASSESSMENTS
Safety screening assessment: As described above (section 8.1), some preexisting allergic 
diseases and other comorbidities that have the potential to increase a participant’s risk of a severe 
allergic reaction or other adverse reaction (e.g., myocarditis or pericarditis) to the study 
vaccinations may be identified during the initial telephone/remote screening process. On a case-
by-case basis, these participants may be asked to come to the NIH after the screening phone call 
to undergo additional clinical studies (e.g., pulmonary function testing, chest X-ray, ECG, 
echocardiogram, flexible nasolaryngoscopy, and/or blood laboratory tests) that are deemed 
necessary by the study team to make sure their comorbid diseases are stable before they undergo 
the study vaccinations. If there are concerns about the stability of any comorbid conditions, the 
participant may be removed from the study.

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Assessment of AEs: Information about AEs will be assessed via appropriate questioning and 
examination at each study contact. Additional procedures may be performed (e.g., clinical 
laboratory evaluations) as needed to further characterize events.
The following specific local and systemic events, as well as symptoms of a potential allergic 
reaction, will be assessed during Visit 1 and Visit 2, and Visits 4 and 5 for participants receiving 
a booster dose. The following mild to moderate events are expected following vaccine 
administration:
-
Local injection site reactions, with the exception of injection site reactions of 
erythema/redness and induration/swelling measuring <2.5 cm
-
Fever
-
Chills
-
Myalgia
-
Arthralgia
-
Fatigue
-
Headache
-
Nausea
-
Vomiting
-
Diarrhea
8.4
SAFETY DEFINITIONS, MANAGEMENT, AND REPORTING 
8.4.1
Definitions
Adverse Event: An AE is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (e.g., abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the subject’s participation in the research, whether or not 
considered related to the research.
Adverse Reaction (AR): An AR means any AE caused (see “Causality” below) by a study 
agent. ARs are a subset of all suspected adverse reactions (SARs; defined below) where there is 
reason to conclude that the study agent caused the event.
Suspected Adverse Reaction (SAR): SAR means any AE for which there is a reasonable 
possibility that the study agent caused the AE.
Per US FDA guidance:  
For the purposes of IND safety reporting, “reasonable possibility” means there is evidence to 
suggest a causal (see “Causality” below) relationship between the study agent and the AE. A 
SAR implies a lesser degree of certainty about causality than an AR, which means any AE 
caused by a study agent.
SARs are the subset of all AEs for which there is a reasonable possibility that the study agent 
caused (see “Causality” below) the event. Inherent in this definition, and in the requirement 

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to report SARs, is the need for the sponsor to evaluate the available evidence and make a 
judgment about the likelihood that the study agent actually caused the AE. 
The sponsor is responsible for making the causality judgment.
Serious Adverse Event: An SAE:

is an AE that results in death.

is an AE that is a life-threatening event (places the subject at immediate risk of death 
from the event as it occurred).

is an AE that requires inpatient hospitalization or prolongs an existing hospitalization.
NOTE:
o
Hospitalization is considered required if outpatient treatment would generally be 
considered inappropriate.
o
Same-day surgical procedures that are required to address an AE are considered 
hospitalizations, even if they do not involve an overnight admission.
o
Hospitalization due to a condition that has not worsened and that pre-dates study 
participation (e.g., elective correction of an unchanged baseline skin lesion), or 
due to social circumstance (e.g., prolonged stay to arrange aftercare), or that is 
planned/required “per protocol” AND that proceeds without prolongation or 
complication, is NOT considered an SAE by this criterion.

is, or results in, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions.

is a congenital anomaly/birth defect/miscarriage/stillbirth.
NOTE: This definition is more inclusive than some commonly published definitions. 
It includes an affected conceptus/neonate whose:
o
biological mother was exposed to a study agent at any point from conception 
through the end of the pregnancy, AND/OR, if breastfeeding, the 30-day neonatal 
period; or
o
biological father was exposed to a study agent at any point during the 90 days 
prior to conception.
This is separate from, and in addition to, general reporting of pregnancy in a study 
participant or female partner of a male participant (see section 8.4.2.3.4 below).

is a medically important event.
NOTE: Medical and scientific judgment should be exercised. Events that significantly 
jeopardize the subject and/or require intervention to prevent one of the SAE outcomes 
listed above are generally considered medically important, and are thus SAEs.
Unexpected Adverse Event: An AE is unexpected if it is not listed in the investigator’s 
brochure or package insert (for marketed products) at the frequency, AND specificity, AND 
severity that has been observed.

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NOTE:
o
Such events should also be evaluated for possible reporting as unanticipated problems 
(UPs) (see section 8.4.2.3.3 below).
o
Unexpected, as used in this definition, also refers to AEs or SARs that are mentioned in 
the investigator’s brochure as occurring with a class of drugs/biologics, or as anticipated 
from the pharmacological properties of the study agent but are not specifically mentioned 
as occurring with the particular study agent under investigation.
Serious and Unexpected Suspected Adverse Reaction (SUSAR): A SUSAR is an SAR 
(defined above) that is both serious and unexpected.
Unanticipated Problem: A UP is any event, incident, experience, or outcome that is:
1. unexpected in terms of nature, severity, or frequency in relation to:
a.
the research (including but not limited to risks) as described in the IRB-approved 
research protocol and informed consent document, investigator’s brochure, or 
other study documents; and
b. the characteristics of the subject population being studied; and is
2. possibly, probably, or definitely related (see “Causality” below) to participation in the 
research; and
3. suggests the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized, per the documents currently approved by the IRB.
NOTE:
o
Per the sponsor, an SAE always meets this “greater risk” criterion.
o
An incident, experience, or outcome that meets the definition of a UP generally 
will warrant consideration of changes to the protocol or informed consent form, or 
to study procedures (e.g., the manual of procedures [MOP] for the study), in order 
to protect the safety, welfare, or rights of participants or others. Some UPs may 
warrant a corrective and preventive action plan (CAPA) at the discretion of the 
sponsor or other oversight entities.
Unanticipated Problem that is not an Adverse Event (UPnonAE): A UPnonAE belongs to a 
subset of UPs that:

meets the definition of a UP, AND

does NOT fit the definition of an AE or an SAE.
NOTE: Examples of UPnonAEs include, but are not limited to:
o
a breach of confidentiality
o
prolonged shedding of a vaccine virus beyond the anticipated timeline
o
unexpectedly large number of pregnancies on a study
o
subject departure from an isolation unit prior to meeting all discharge criteria
o
accidental destruction of study records
o
unaccounted-for study agent

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o
overdosage, underdosage, or other significant error in administration or use of 
study agent or intervention, even if there is no AE/SAE
o
development of an actual or possible concern for study agent purity, sterility, 
potency, dosage, etc
NOTE: A decision to temporarily quarantine, or to permanently not use all or 
part of study agent supply due to an unexpected finding or event (e.g., 
particulate, cloudiness, temperature excursion), even if there is no known or 
proven issue (i.e., out of an “abundance of caution”), is considered a 
UPnonAE.
Protocol Deviation: Any change, divergence, or departure from the IRB-approved research 
protocol.
1. Major Deviations: Deviations from the IRB-approved protocol that have, or may have 
the potential to, negatively impact the rights, welfare, or safety of the subject, or to 
substantially negatively impact the scientific integrity or validity of the study.
2. Minor Deviations: Deviations that do not have the potential to negatively impact the 
rights, safety, or welfare of subjects or others, or the scientific integrity or validity of the 
study.
Non-compliance: Failure of an investigator to follow the applicable laws, regulations, or 
institutional policies governing the protection of human subjects in research, or the requirements 
or determinations of the IRB, whether the failure is intentional or not.

Continuing non-compliance: A pattern of recurring non-compliance that either has 
resulted, or, if continued, may result in harm to subjects or otherwise materially 
compromise the rights, welfare and/or safety of subjects, affect the scientific integrity of 
the study or validity of the results. The pattern may comprise repetition of the same non-
compliant action(s), or different non-compliant events. Such non-compliance may be 
unintentional (e.g. due to lack of understanding, knowledge, or commitment), or 
intentional (e.g. due to deliberate choice to ignore or compromise the requirements of any 
applicable regulation, organizational policy, or determination of the IRB).

Serious non-compliance: Non-compliance, whether intentional or not, that results in 
harm or otherwise materially compromises the rights, welfare and/or safety of the subject. 
Non-compliance that materially affects the scientific integrity or validity of the research 
may be considered serious non-compliance, even if it does not result in direct harm to 
research subjects.
Events of Special Interest (ESIs) and Protocol-Specified Exempt Events (PSEEs): ESIs and 
PSEEs are events, identified in detail within the protocol and specified in advance, that will be 
handled in a protocol/study-specific manner that differs from statutory and general rules for 
reporting. These events may include, but are not limited to:

laboratory values

clinical findings

statutory AEs or SAEs per the standard definition

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
hospitalizations and procedures
ESIs are protocol/study-specific rules for events that are of particular concern (due to population, 
study intervention, class effect, etc). Reporting is generally enhanced/upgraded beyond the 
general standard.
PSEEs are protocol/study-specific rules for events that are, to some degree, expected/anticipated 
(due to population or condition under study, concomitant treatments, etc). Reporting is generally 
downgraded/diminished from the general standard.
(See section 8.4.2 for special handling of ESIs and/or PSEEs in this protocol.)
8.4.2
Documenting, Assessing, Recording, and Reporting Events
All AEs, including those that may appear to have a non-study cause (see “Causality” below), will 
be documented (e.g., on the clinical chart/progress notes/clinical laboratory record), recorded 
(e.g., research database), and reported (e.g., cumulatively from the research database, or 
according to protocol-specified expedited reporting mechanism) to the sponsor from the time 
informed consent is obtained through the timeframe specified below. At each contact with the 
subject, information regarding AEs will be elicited by open-ended questioning and examinations.
AEs and SAEs will generally be recorded, assessed, and reported according to the timeframes 
stated in the protocol and followed up as outlined in Table 2. Descriptions of PSEEs and ESIs 
and timeframes for assessing and reporting these events are outlined in Table 3 and Table 4.
Table 2: Standard Times for Follow-up of Events
Event type
Follow events through
Related SAEs
End of subject participation in study, or if 
study personnel become aware thereafter
Unrelated SAEs
End of subject participation in study 
Related non-serious AEs of grade 1 to 3
End of subject participation in study
All other related non-serious AEs
End of subject participation in study
Unrelated non-serious AEs
End of subject participation in study
Table 3: PSEE List and Reporting
Event description
How event will be reported
CoFAR Grade 1-3 allergic reaction
As an AE unless it meets statutory SAE 
criteria where it will be reported as an SAE. 
(All CoFAR Grade 4 events will be reported 
as SAEs.)

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Table 4: ESI List and Reporting
Event description
How event will be reported
1. A single occurrence of an event that is 
uncommon and known to be strongly 
associated with vaccine exposure (e.g., 
Stevens-Johnson Syndrome, Guillain-Barré 
syndrome); 
2. One or more occurrences of an event that 
is not commonly associated with vaccine 
exposure, but is otherwise uncommon in 
the population exposed to the drug (e.g., 
tendon rupture);
3. A single occurrence of myocarditis or 
pericarditis of any grade.
The ESI will be reported as an 
SAE/expeditedly even if it does NOT meet 
statutory SAE criteria.
8.4.2.1
Investigator Assessment of Adverse Events
The investigator will initially assess all AEs with respect to seriousness (according to SAE 
definition above), severity (intensity or grade, see below), and causality (relationship to study 
agent and relationship to participation in the research, see below). The Clinical Safety Office 
(CSO)/sponsor medical monitor (SMM) is responsible for final/regulatory determinations of 
expectedness and causality.
8.4.2.1.1
Severity Grading
The CoFAR scale will be used to grade the severity of allergic reactions. The investigator will 
grade the severity of other AEs, including laboratory and testing abnormalities and results, 
according to the “Common Terminology Criteria for Adverse Events (CTCAE)” (v 5.0) which 
can be found at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
Events that are NOT gradable using the above specified table will be graded as follows:

Mild = grade 1

Moderate = grade 2

Severe = grade 3

Potentially life threatening = grade 4

Death = grade 5
NOTE: A subject death should always be reported as grade 5.
8.4.2.1.1.1
Laboratory Value Assessment and Clinical Significance Criteria
Except as specified below, all abnormal lab values of grade 1 or above are reportable.

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Grade 1 and 2 abnormal laboratory values are considered clinically significant, and are to be 
recorded in the research database, and reported, if they meet one or more of the following 
criteria: 

result in a study agent dosage adjustment, interruption, or discontinuation

are accompanied by clinically abnormal signs or symptoms that are likely related to the 
laboratory abnormality (e.g., clinical jaundice)

indicate a possible organ toxicity (e.g., elevated serum creatinine)

result in additional/repeat testing or medical intervention (procedures/treatments) (e.g., 
EKG to evaluate arrhythmia potential with a high serum potassium; one or more EKGs to 
assess an elevated troponin level; potassium supplementation for hypokalemia)

indicates possible over-dosage 

are considered clinically significant by the investigator or SMM
8.4.2.1.2
Causality
Causality (likelihood that the event is caused by the study agents) will be assessed by the 
principal investigator considering the factors listed under the following categories:
Definitely Related

reasonable temporal relationship

follows a known response pattern

clear evidence to suggest a causal relationship

there is no alternative etiology
Probably Related

reasonable temporal relationship

follows a suspected response pattern (based on similar agents)

no evidence of a more likely alternative etiology
Possibly Related

reasonable temporal relationship

little evidence for a more likely alternative etiology
Unlikely Related

does not have a reasonable temporal relationship
AND/OR

there is good evidence for a more likely alternative etiology

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Not Related

does not have a temporal relationship
AND/OR

definitely due to an alternative etiology
Note: Other factors (e.g., dechallenge, rechallenge, if applicable) should also be considered for 
each causality category when appropriate. Causality assessment is based on available 
information at the time of the assessment of the AE. The investigator may revise the causality 
assessment as additional information becomes available.
Causality assessment will be reviewed by the sponsor. The sponsor may make a separate and 
final determination on the “reasonable possibility” that the event was “related” (comprising 
definitely, probably, and possibly related) or “unrelated” (comprising unlikely and not related) to 
the study agent, in keeping with applicable (US FDA) guidance on sponsor IND safety reporting.
8.4.2.2
Recording of Events
AEs will be promptly recorded in the research database, regardless of possible relationship to 
study interventions. If a diagnosis is clinically evident (or subsequently determined), the 
diagnosis rather than the individual signs and symptoms or laboratory abnormalities will be 
recorded as the AE. The investigator will review events regularly to ensure they have been 
captured correctly and to perform assessment of events individually and cumulatively to assess 
possible safety trends.
8.4.2.3
Investigator Reporting Responsibilities
The principal investigator and/or equally qualified designee will check daily for events that may 
require expedited reporting. 
The principal investigator and/or equally qualified designee will also monitor all accumulating 
data no less than weekly, or according to superseding NIH or NIAID policy, whichever is more 
frequent.
Data will be reviewed by the principal investigator/designee on a regular basis for accuracy and 
completeness. 
Data will be submitted to the sponsor in keeping with all applicable agreements and when 
requested, such as for periodic safety assessments, review of IND annual reports, review of IND 
safety reports, and preparation of final study reports.
The principal investigator will ensure prompt reporting to safety oversight bodies (e.g., CSO, 
DSMB), regulatory entities, and stakeholders as specified below, and according to any additional 
requirements or agreements.
8.4.2.3.1
Adverse Events
Unless otherwise specified above, AE data will be entered into the research database no less than 
every other week and will include all data through one week prior to database entry.

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8.4.2.3.2
Serious Adverse Events (Expedited Reporting)
Unless otherwise specified above, all SAEs (regardless of relationship and whether or not they 
are also UPs) must be reported to the CSO as specified by the CSO (e.g., REDCap; use the 
Safety Expedited Report Form [SERF]/email if REDCap is not available). If the 
preferred/indicated mechanism for reporting is not available, the CSO/SMM should be contacted 
by telephone, fax, or other reasonable mechanism to avoid delays in reporting. ESIs will be 
reported in the same timeframe and mechanism as an SAE even though they do not meet the 
statutory SAE definition.
CSO CONTACT INFORMATION:
Clinical Safety Office
5705 Industry Lane
Frederick, MD 21704
Phone: 301-846-5301
Fax: 301-846-6224
Email: rchspsafety@mail.nih.gov 
https://crimsonredcap.cc.nih.gov/redcap/index.php
Deaths and immediately life-threatening SAEs must be reported to the CSO promptly, and no 
later than the first business day following the day of study personnel awareness. 
All other SAEs must be reported to the CSO no later than the third business day following the 
day of study personnel awareness.
If an individual subject experiences multiple SAEs in a closely timed/overlapping “cause-and-
effect” (cascade) sequence, the principal investigator, after careful evaluation, will report ONLY 
primary/precipitating event(s) individually. SAEs that are determined to be definitely secondary 
to other SAEs will be detailed in the narrative portion of the report of the relevant 
primary/precipitating SAE. A clinical rationale and findings to support such reporting should be 
part of the narrative. 
For each SAE report, the research database entry MUST match the corresponding entries on the 
SAE report (e.g., start and stop dates, event type, relationship, and grade), and must be updated 
if necessary (e.g., if the SAE report was generated after the corresponding AE was entered in the 
research database).
Unless otherwise specified above, SAEs that have not resolved by the end of the per-protocol 
follow-up period for the subject are to be followed until final outcome is known (to the degree 
permitted by the IRB-approved informed consent form). If it is not possible to obtain a final 
outcome for an SAE (e.g., the subject is lost to follow-up), and to update the CSO, the last 
known status and the reason a final outcome could not be obtained will be recorded by the 
investigator on an SAE report update and the CRF.

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8.4.2.3.3
Unanticipated Problems
Unless otherwise specified above, UPs that are also AEs or SAEs, must be reported to the CSO 
(by REDCap, or by email and SERF if REDCap is not available) no later than when they are due 
to be reported to the IRB.
UPnonAEs are not reported to the CSO but must be reported to the clinical trials management 
(CTM) group and the IRB according to their requirements and preferred methods. If the 
UPnonAE raises a significant potential subject safety concern, the SMM should be consulted by 
email or phone no later than when the report is made to CTM.
8.4.2.3.4
Pregnancy
Pregnancy testing will be performed prior to the first study vaccination. If the result is positive, 
the participant will be withdrawn from the study, and no additional follow-up will be performed.
8.4.2.4
Sponsor’s Reporting Responsibilities
Events reported to the sponsor will be promptly evaluated and will be reported as required 
according to FDA IND safety reporting guidance and regulations. IND safety reports will be sent 
to other investigators conducting research under the same IND and will be shared with other 
stakeholders according to applicable agreements (e.g., CRADAs and CTAs).
The sponsor will also submit an IND annual report of the progress of the investigation to the 
FDA as defined in 21 CFR 312.33.
All UPs will be evaluated by the sponsor, and a summary of the event, and any necessary 
(corrective/preventative) actions, will be distributed to investigators conducting research under 
the same IND as may be relevant and appropriate.
8.4.3
Withdrawal Criteria for an Individual Subject
An individual subject will be withdrawn from the study for any of the following:

An individual subject’s decision. (The investigator should attempt to determine the 
reason for the subject’s decision.)

Non-compliance with study procedures or requirements (see sections 5.5 and 6.5) to the 
extent that it is potentially harmful to the subject or to the integrity of the study data, per 
investigator discretion.

The investigator determines that continued participation in the study would not be in the 
best interest of the subject.
The reason for participant withdrawal will be recorded in the research database.
8.4.3.1
Re-enrollment and Unplanned Procedure Repetition
Unless otherwise specified within this protocol, each person who is a subject in this study may 
be enrolled, and may pass through each step and process outlined in the protocol, only ONCE 
(i.e., subjects may not “go back” and repeat a protocol step already completed). On a case-by-
case basis, a request for re-enrollment, or for repetition of a protocol step or procedure already 

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completed, may be submitted to, reviewed by, and approved by the SMM in writing. The SMM 
may also recommend or require consultation of the IRB and/or DSMB.
8.4.3.2
Replacement of Withdrawn Subjects or Subjects Who Discontinue Study 
Agent 
Subjects who are withdrawn from the study or discontinue study vaccinations will not be 
replaced.
All subjects exposed to study agents must be included in the safety dataset.
8.4.4
Additional Safety Oversight
8.4.4.1
Safety Review and Communications Plan
A safety review and communication plan (SRCP) is required for this protocol. The SRCP is an 
internal communications document between the principal investigator and the CSO, as sponsor 
representative, which delineates key safety oversight responsibilities of the principal investigator, 
the CSO, and other stakeholders. The SRCP includes a plan for conducting periodic safety 
surveillance assessments by the CSO.
8.4.4.2
Sponsor Medical Monitor
A SMM, representing the sponsor, has been appointed for oversight of safety in this clinical 
study. The SMM will be responsible for performing safety assessments as outlined in the SRCP.
8.4.4.3
Oversight Committees
8.4.4.3.1
Data and Safety Monitoring Board
The NIAID intramural data and safety monitoring board (DSMB) includes independent experts 
that do not have direct involvement in the conduct of the study and have no significant conflicts 
of interest as defined by NIAID policy. The DSMB will review the study protocol, consent 
document, and investigator brochure prior to initiation and twice a year thereafter, or as may be 
determined by the DSMB. In addition, the DSMB will review unblinded data after the first 5 
participants complete study vaccinations or after the first 4 months (whichever comes first), and 
every 4 months thereafter (or after every 20 participants completes study vaccinations, 
whichever comes first). The DSMB can make a variety of recommendations, such as: 1) stop the 
trial because of safety concerns, either based on the halting rules or based on results that are 
similarly concerning to those established in the halting rules, 2) stop the trial if there appears to 
be little value in proceeding (e.g., inability to recruit participants or if no reactions occur after, 
perhaps, 40 subjects have been evaluated), 3) continue the trial, but announce the topline interim 
results to the public, if timely release of the data will provide important guidance to the 
community, or 4) continue the trial without modification.
The DSMB may convene additional reviews as necessary or per principal investigator request to 
evaluate the safety, efficacy, study progress, and conduct of the study. 
All deaths, SAEs, UPs, pregnancies, and IND safety reports will be reported to the DSMB at the 
same time they are submitted to the IRB and CSO unless otherwise specified herein. A summary 
of PSEEs will also be provided for review by the DSMB along with study documents submitted 
for periodic scheduled DSMB reviews.

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All cases of intentional or unintentional unblinding will be reported to the DSMB not later than 
one business day from the time of study personnel awareness. 
The principal investigator will notify the DSMB at the time pausing or halting criteria are met 
and obtain a recommendation concerning continuation, modification, or termination of the study. 
The principal investigator will submit the written DSMB summary reports with 
recommendations to the IRB.
8.4.5
Pausing Rules
“Pausing” is discontinuation of study vaccinations in a single subject. Other than discontinuation 
of study vaccinations, subjects will continue to be followed per protocol during a pause.
The pausing criterion for individual subjects in this study is the following:

A subject experiences CoFAR Grade 4 allergic reaction to the first study vaccination.

A subject experiences an ESI or an SAE assessed as being caused by the vaccine/placebo 
(unless the event is a PSEE).   
The principal investigator or the CSO may also pause dosing/study interventions for one or more 
subjects for any safety issue. The DSMB may recommend a pause to the CSO.
8.4.5.1
Reporting a Pause
If a pausing criterion is met, a description of the AE(s) or safety issue must be reported by the 
principal investigator within 1 business day to the CSO and the IRB according to their 
requirements. The principal investigator will also notify the DSMB.
8.4.5.2
Resumption Following a Pause
If the pausing criterion is met following the first study vaccination, the second study vaccination 
will not be administered to that participant, but the other remaining study procedures will 
proceed as scheduled. The CSO, in collaboration with the principal investigator and DSMB or 
other safety review entity, will determine if any additional modifications or requirements may 
apply, for the impacted subject(s), or whether the events that triggered the pause require 
expansion to a study halt (see below).
The CSO or sponsor designee will notify the principal investigator of the decision. The principal 
investigator will notify the IRB of the decision according to the IRB’s process.
8.4.5.3
Discontinuation of Study Agent
Discontinuation of study vaccination does not mean discontinuation from the study, and 
remaining study procedures may be completed as indicated by the study protocol if the subject is 
willing to remain on study.
8.4.6
Halting Rules for the Protocol
“Halting” is discontinuation of study vaccinations for all subjects in a study and suspension of 
enrollment until a decision is made to either resume or permanently discontinue such activity. 

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Subjects who have already received a study vaccination at the time of a halt will continue to be 
followed per protocol.
The halting rules are:

More than 3 subjects experience a CoFAR Grade 4 allergic reaction and the frequency of 
Grade 4 allergic reactions is more than 10% of subjects enrolled to date;
OR

Any safety issue that the principal investigator or the CSO determines should halt the 
study. The DSMB may recommend a halt to the CSO;
OR

Any death.
In addition, the FDA or any regulatory body having oversight authority may halt the study at any 
time. The DSMB may recommend a study halt.
8.4.6.1
Reporting a Study Halt
If a halting criterion is met, a description of the AE(s) or safety issue must be reported by the 
principal investigator within 1 business day to the CSO and the IRB according to their 
requirements. The principal investigator will also notify the DSMB.
8.4.6.2
Resumption of a Halted Study
If a halting criterion is met, enrolled subjects who have received a study vaccination will 
continue with the remaining study procedures (other than study vaccinations) as scheduled. The 
principal investigator, CSO, and DSMB will discuss the option of continuing the study but 
administering the study agent in graded doses (10% of full dose, observe 30 minutes, and then 
administer remaining dose), or whether any other study modifications should be made.
The CSO or sponsor designee will notify the principal investigator of the decision. The principal 
investigator will notify the IRB of the decision according to the IRB’s process.
8.4.6.3
Discontinuation of Study
The study will be stopped permanently for a single Grade 5 reaction. Subjects will continue to be 
followed for protocol-specified safety assessments or as clinically indicated, whichever is more 
conservative.
8.5
UNANTICIPATED PROBLEMS.
8.5.1
Definition of Unanticipated Problems
The definition of a UP is provided in section 8.4.1.
8.5.2
 Unanticipated Problem Reporting 
The investigator will report UPs to the NIH IRB as per Policy 801.
8.5.3
NIH Intramural IRB Reporting of IND Safety Reports
Only IND Safety Reports that meet the definition of a UP will need to be reported to the NIH 
Intramural IRB.

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9
STATISTICAL CONSIDERATIONS
The analysis will be primarily aimed at estimation and description. There is considerable 
uncertainty about the number of subjects that can actually be enrolled, so both the sample size 
rationale and planned analysis are written to take that uncertainty into account. There is no intent 
to write a formal Statistical Analysis Plan.
9.1
STATISTICAL HYPOTHESIS
The primary goal is estimation of the primary and secondary endpoints, and estimation of the 
difference in endpoints between the active and placebo vaccines. Statistical hypothesis testing 
will be done to compare active versus placebo vaccines, but this is secondary to estimation.
The endpoints are as follows, and are defined in greater detail previously in the protocol 
(sections 1.1 and 3):  
Primary Endpoint: 

Proportion with systemic allergic reaction to the active (ie, Pfizer-BioNTech) vaccine 
dose delivered in this study
Secondary Endpoints:

Proportion with severe systemic allergic reaction to the COVID-19 vaccine dose 
delivered in this study

Proportion with mild/moderate systemic allergic reaction to the COVID-19 vaccine dose 
delivered in this study

Proportion with anaphylactic reaction to the COVID-19 vaccine dose delivered in this 
study

Proportion with systemic allergic reaction to each study vaccination (i.e. active and 
placebo/pre- and post-crossover) by arm

Proportion with more (or less) severe systemic allergic reaction to the COVID-19 vaccine 
dose delivered in this study than recorded reaction to the first full COVID-19 vaccine 
dose
9.2
SAMPLE SIZE DETERMINATION
The goal is to enroll up to 100 subjects; however, realistically, it may only be possible to enroll a 
smaller cohort. The ability to recruit for this study will depend on the rarity of such allergic 
reactions in the population and the acceptability of repeat vaccination and a 4-day hospital stay 
among individuals who have had these reactions. Current data indicates an extremely low 
systemic reaction rate, although it is likely that the overall rate may be higher since individuals 
recruited for this study have a history of a systemic allergic reaction following administration of 
the first dose of the vaccine. In sum, the study will provide more precise estimates with greater 
enrollment; however, even if fewer than 100 subjects enroll, the resulting data will provide 
valuable new information.  
Since the primary goal of the study is estimation, we present the following example exact 
confidence intervals as a function of varying sample size and varying outcomes to illustrate 
achievable precision of estimates. We present such confidence intervals for the primary endpoint, 

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and also estimation of the risk difference of active vaccine versus placebo vaccine. The 
difference between active and placebo can be estimated in 2 different ways: one compares the 
results in the randomized arms at the first shot; and the other compares results within a subject 
across the 2 study vaccinations, exploiting the crossover design. Tables below present a subset of 
example scenarios in the study.   
Table 5: Exact 95% Clopper Pearson Confidence Intervals for Primary Outcome, by 
Sample Size and Proportion with Systemic Allergic Reaction to Second Dose
 Total N
Observed Reaction Rate
.00
.20
.40
.60
.80
1.00
5
0-0.522
0.005-0.716
0.053-0.853
0.147-0.947
0.284-0.995
0.478-1
10
0-0.308
0.025-0.556
0.122-0.738
0.262-0.878
0.444-0.975
0.692-1
15
0-0.218
0.043-0.481
0.163-0.677
0.323-0.837
0.519-0.957
0.782-1
20
0-0.168
0.057-0.437
0.191-0.639
0.361-0.809
0.563-0.943
0.832-1
40
0-0.088
0.091-0.356
0.249-0.567
0.433-0.751
0.644-0.909
0.912-1
60
0-0.06
0.108-0.323
0.276-0.535
0.465-0.724
0.677-0.892
0.94-1
80
0-0.045
0.119-0.304
0.292-0.516
0.484-0.708
0.696-0.881
0.955-1
100
0-0.036
0.127-0.292
0.303-0.503
0.497-0.697
0.708-0.873
0.964-1
As the sample size increases, precision in the estimate of the true proportion of subjects with a 
reaction to the second vaccine dose also increases. As an example, if the total N is 10, and there 
is .20 reaction rate (i.e., 2 react) to active vaccine, then the 95% CI for reaction rate is (.025, 
.556).
Table 6: Exact 95% Confidence Intervals for the Difference in Reaction Rate Between 
Vaccine and Placebo Arms on Day 1
Total N
Observed Reaction Rate per Arm on Day 1
 
1.00 Vaccine, 
  .00 Placebo
  .80 Vaccine,
 .20 Placebo
.60 Vaccine, 
.20  Placebo
6
0.082-1
-0.282-0.992
-0.554-0.889
10
0.383-1
-0.112-0.933
-0.268-0.858
20
0.663-1
0.127-0.862
-0.058-0.756
40
0.824-1
0.287-0.798
0.084-0.666
60
0.881-1
0.313-0.767
0.134-0.622
80
0.702-1
0.338-0.748
0.144-0.594
100
0.597-1
0.355-0.734
0.16-0.575
Note: If only 6 subjects are enrolled, a reaction rate of 80% in the vaccine arm corresponds to 3/3 reactions; a reaction rate of 
60% in the vaccine arm corresponds to 2/3 reactions; and a reaction rate of 20% in the placebo arm corresponds 1/3 reactions.  
Thus, if the total N is 20 with 10 on active vaccine on Day 1 and 10 on placebo, and 8 of those 
receiving active vaccine have a reaction and 2 of those receiving placebo have a rection, the 95% 
CI for the excess reaction in active vaccine minus placebo is (.127, .862). Since this particular 
confidence interval does not include zero, this is also a demonstration that vaccines lead to 
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Table 7: Exact 95% Confidence Intervals for the Risk Difference Comparing each 
Individual’s Vaccine Phase to Placebo Phase Response Using McNemar’s Approach
Total N
Observed Reaction Rate per Treatment Phase
 
1.00 Vaccine, 
  .00 Placebo
  .80 Vaccine,
 .20 Placebo
.60 Vaccine, 
.20  Placebo
5
-0.044-1
-0.275-0.947
-0.369-0.853
10
0.338-1
0.04-0.878
-0.088-0.738
15
0.517-1
0.162-0.837
0.026-0.677
20
0.621-1
0.235-0.809
0.084-0.639
40
0.797-1
0.369-0.751
0.192-0.567
60
0.861-1
0.423-0.724
0.238-0.535
80
0.895-1
0.453-0.708
0.264-0.516
100
0.915-1
0.473-0.697
0.281-0.503
The examples above assume that if a subject reacts to the placebo phase, they will also react to 
the active vaccine phase. For example, with 10 subjects, and a reaction rate of 80% in the active 
vaccine and 20% in the placebo, this means that 2 subjects react to both active vaccine and 
placebo, 6 subjects react only to active vaccine, and 2 subjects react to neither. And, in this 
example the 95% confidence interval for excess reaction rate in active vaccine minus placebo is 
(.04, .878). The confidence intervals in this table are narrower than the ones in the previous table, 
since they use information from both study vaccinations. (There are other scenarios to get the 
same reaction rates [i.e. in the previous example, 1 subject reacts to both active vaccine and 
placebo, 7 subjects react only to active vaccine, 1 subject reacts only to placebo, and 1 subject 
reacts to neither], but these alternatives are not presented here, and the confidence intervals 
would be slightly different.) 
While hypothesis testing will be done comparing active vaccine and placebo reactions, this goal 
is viewed as secondary to estimation of the difference.  
9.3
POPULATIONS FOR ANALYSES
The modified intention-to-treat analysis data set includes all subjects who receive the first 
injection in the study and are followed for the initial 3 hours for systemic allergic reaction. 
9.3.1
Evaluable for Toxicity 
All participants will be evaluable for toxicity from the time of their first study vaccination.
9.3.2
Evaluable Non-Target Disease Response
Not applicable
9.4
STATISTICAL ANALYSES
9.4.1
General Approach
Most analyses will result in estimates of binary endpoints and will be presented as proportions 
and corresponding exact 95% confidence intervals.

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Exploratory endpoints, such as mechanistic endpoints, will be presented as means with standard 
deviations and/or as medians and interquartile ranges. Graphical presentation may be useful.
While hypothesis testing is likely to be limited in scope, two-sided p-values with alpha=.05 will 
be used, with appropriate cautions regarding interpretation due to multiplicity.  
9.4.2
Analysis of the Primary Endpoints
The primary endpoint will be estimated using the proportion of reaction to the active vaccine, 
and presented with a 95% confidence interval, using the Clopper-Pearson method.
It is not anticipated that individuals randomized to receive placebo vaccination first will not get 
the active vaccine, but if this occurs, the following approaches will be used: i) analysis in the 
population with complete data (which will be the primary approach), and ii) analysis where 
missing data is imputed to be a vaccine reaction.
9.4.3
Analysis of the Secondary Endpoint(s)
Analyses to simple single proportion estimates will follow the same approach described for the 
primary endpoint.
Analysis of risk difference between active and placebo vaccines will be addressed in 2 separate 
ways. First, using only data from the first study vaccination, the risk difference will be estimated 
(proportion with systemic reaction in the active vaccine arm minus the analogue in the placebo 
arm) with an unconditional exact confidence interval. The second approach will exploit the 
crossover design (i.e., comparing each individual’s active vaccine to placebo response), by 
estimating the risk difference using a McNemar’s approach to an exact confidence interval.[34] 
While the McNemar’s approach should be more precise than the group comparison approach at 
the first study vaccination, the potential for missing data on the second study vaccination, 
especially in the initial vaccine arm is not ideal. If there are such missing data, the second study 
vaccination will be imputed in the most extreme ways (i.e., smallest risk difference and largest 
risk difference) to see if the results are robust.  
Hypothesis testing can be done for the active vaccine versus placebo risk difference. A Fishers 
exact test will be done when comparing the randomized arm at the first study vaccination. An 
exact McNemar’s test will be done when comparing the within-subject differences. Approaches 
to missing data for McNemar’s follow the estimation approaches.  
A signed rank test will also be done to compare severity of reaction at the first vaccine (i.e., done 
prior to enrollment) to active study vaccine (where the difference in grade is the metric). Since 
that analysis assumes grade is linear, these data will also be analyzed using a purely ordinal 
approach to grade using a longitudinal GEE model with a cumulative logit link; this is 
effectively a generalization of McNemar’s test, but for ordinal instead of binary data. Tabular 
data will also be presented.
9.4.4
Safety Analyses
The primary and secondary endpoints of this study are focused on safety and will be evaluated 
and analyzed as described above. Allergic reactions will be scored using the CoFAR Grading 
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AEs following active vaccine administration are expected as described in Section 2.3.1, and will 
be assessed during the participant’s ICU stay as well as the remote follow-up within 1 week post-
discharge (Visit 2) and at the in-person follow-up visits (Visits 3, 4, and 6). Efforts will be made 
to record start and stop dates of all AEs (both allergic and nonallergic in nature), severity, 
relationship to the study intervention, and expectedness based on study intervention. If 
participants experience a CoFAR Grade 4 or higher reaction on Day 1, or any life-threatening 
adverse reaction related or unrelated to the study intervention, then no additional dosing will 
occur and participants will be followed per study protocol.
9.4.5
Baseline Descriptive Statistics
Baseline descriptive statistics will be presented in terms of proportions, means/medians, standard 
deviations/interquartile ranges. Unless enrollment is very limited in size, the baseline variables 
will also be presented by randomized arm.
9.4.6
Planned Interim Analyses
No formal interim analyses are planned.
9.4.7
Sub-Group Analyses
The baseline characteristics of the cohort will be described. If the number of enrolled patients is 
sufficient, endpoints will be analyzed in subgroups (e.g., gender; age; ethnicity; severity of 
reaction to original vaccine dose; menopausal status for female participants; presence, type, and 
severity of allergic diseases; laboratory assessments of allergic sensitization and inflammation; 
history of allergic reactions including cause, severity, and treatment required; presence, type, and 
levels of anti-PEG antibodies; history of prior SARS-CoV-2 infection; other medical 
comorbidities; medication use; presence of genetic variants that may influence response to 
vaccine including but not limited to hereditary alpha tryptasemia; level of inflammatory and 
immune markers at baseline). 
9.4.8
Tabulation of individual Participant Data
Individual patient data may be listed, especially if enrollment is limited.
9.4.9
Exploratory Analyses
Baseline mechanistic endpoints and other potential risk factors including results of mental health 
and anxiety assessments as well as changes in these endpoints pre- and post-vaccine will be 
described and compared between those with and without systemic allergic reactions (and 
likewise for other allergic endpoints). Analyses will generally use Wilcoxon rank sum tests when 
comparing groups and signed rank tests when comparing within subjects (e.g., pre- versus post-
vaccine), however parametric tests might be used if number of enrolled patients is sufficient.
The ability to do hypothesis testing and modelling of risk factors and changes in exploratory 
endpoints pre- and post-vaccine will depend on the number of subjects enrolled. The proportion 
of subjects who react to the study-administered booster dose (among those who receive it), will 
be computed along with the corresponding 95% confidence interval, using the Clopper-Pearson 
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10 REGULATORY AND OPERATIONAL CONSIDERATIONS
10.1
INFORMED CONSENT PROCESS
10.1.1
Consent/Assent Procedures and Documentation
Informed consent is a process where information is presented to enable persons to voluntarily 
decide whether or not to participate as a research subject. It is an ongoing conversation between 
the human research participant and the researchers which begins before consent is given and 
continues until the end of the participant’s involvement in the research. Discussions about the 
research will provide essential information about the study and include purpose, duration, 
experimental procedures, alternatives, risks, and benefits. Coercion and undue influence will be 
minimized by informing participants that their decision to join the study will not affect any 
medical care they are currently receiving at the NIH, or their eligibility to participate in other 
research studies at the NIH. Participants will be given as much time as they need to read the 
consent form and ask questions of the investigators. Participants will also be given time to 
discuss their participation with family members, friends, and other healthcare providers.
Informed consent will be obtained in person or remotely via telephone or NIH-approved 
videoconference platform, by a study team member authorized to obtain consent. Whether in 
person or remote, the privacy of the subject will be maintained. Consenting investigators (and 
participant, when in person) will be located in a private area (e.g., clinic consult room). When 
consent is conducted remotely, the participant will be informed of the private nature of the 
discussion and will be encouraged to relocate to a more private setting if needed. When consent 
is obtained in person, participants and investigators may view the same approved consent 
document either as hard copy or by viewing an electronic version on a monitor, or they may view 
individual copies of the approved consent document as hard copies or on separate screens.
The participants will sign the informed consent document prior to undergoing any research 
procedures (except some screening procedures, as described in section 8.1). Consent will be 
documented with required signatures on the hard copy of the consent form or on the electronic 
document. When a document that is in electronic format is used for the documentation of 
consent, this study will use the iMed platform to obtain the required signatures. This platform is 
compliant with 21 CFR Part 11. The identity of the participant will be determined by a prompt 
which will require the provision of information from an official identification document, prior to 
obtaining the signature. Signatures can be captured via iMed either onsite at the CC via a 
signature pad, or remotely via the iMed Mobile Signature Capture that can be sent via email or 
text.
A copy of the informed consent document will be given to the participants for their records. The 
consenting investigator will document the signing of the consent form in the participant’s 
medical record. The investigator will confirm that written legally effective consent has been 
obtained prior to initiating any study interventions.
The rights and welfare of the participants will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this 
study. The participants may withdraw consent at any time throughout the course of the trial.

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After September 15, 2022, a consent addendum will be reviewed with participants at Visit 4. 
This addendum will provide additional information about the potential for booster vaccination 
with the monovalent formulation or newly authorized bivalent formulation of the Pfizer-
BioNTech vaccine. The process for review and signing of this consent addendum will be same as 
that described above for the informed consent document.
Remote consent process: When the informed consent process occurs remotely, the informed 
consent document will be sent via secure email, file transfer, or NIH-approved platform to the 
potential participant prior to the consent discussion. An explanation of the study will be provided 
over the telephone or NIH-approved videoconference method (e.g., Microsoft Teams) after the 
participant has had the opportunity to read the consent form. During the consent process, 
participants and investigators will view the same approved consent document simultaneously in 
their respective locations, or they will view individual copies of the approved consent document 
on screens or as hard copies at their respective locations. The participant can sign and date the 
hard copy, print the electronic form to sign and date in ink, or they can sign and date the 
electronic document as described above. 
The participant will return the signed and dated consent form to the consenting investigator, who 
will sign and date it with the date it was received. The consent form can either be printed and 
signed and dated in ink, or the electronic document can be signed and dated as described above. 
A fully executed copy will be sent to the participant for their records.
Assent process: Minor participants will be included in all discussions about the study, and age-
appropriate language will be used to describe the procedures and tests involved in this study, 
along with the risks, discomforts, and benefits of participation. Minor participants aged 16 or 17 
years will provide assent by signing a hard copy or electronic copy of the informed consent 
document, as described above. The parent(s)/legal guardian(s) will provide permission for the 
minor participant to participate by signing a hard copy or electronic copy of the consent form, as 
described above. The consent/assent process will be documented in the minor participant’s 
medical record.
10.1.2
Consent for Minors When They Reach the Age of Majority
When a pediatric subject reaches age 18, continued participation (including ongoing interactions 
with the subject or continued analysis of identifiable data) will require that consent be obtained 
from the now adult with the standard protocol consent document to ensure legally effective 
informed consent has been obtained.
If reconsent is not feasible, we request waiver of informed consent to continue to use data and/or 
specimens for those individuals who become lost to follow up or who have been taken off study 
prior to reaching the age of majority.
Requirements for Waiver of Consent consistent with 45 CFR 46.116(f)(3):
(1) The research involves no more than minimal risk to the subjects.
a.
Analysis of samples and data from this study involves no additional risks to 
subjects.
(2) The research could not practicably be carried out without the waiver or alteration.

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a.
Considering the length of time between the minor’s last contact with the 
research team and their age of majority, it will likely be very difficult to locate 
them again. A significant reduction in the number of samples analyzed is 
likely to impact the quality of the research. 
(3) As the research involves using identifiable private information or identifiable 
biospecimens, the research could not practicably be carried out without using such 
information or biospecimens in an identifiable format. 
a.
Though the purpose of future studies cannot yet be known, they often involve 
the correlation of clinical outcomes and clinical interventions with laboratory 
studies. Such information would be unavailable if access to medical record 
numbers was unavailable. 
(4) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects.
a.
Retention of these samples or data does not affect the welfare of subjects. 
(5) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation.
a.
We only request a waiver of consent for those subjects who have been lost to 
follow-up or who have been taken off study prior to reaching the age of 
majority.
10.1.3
Considerations for Consent of NIH Staff, or Family Members of Study Team 
Members
Consent for NIH staff and family members of the study team will be obtained as detailed above 
and will comply with the requirements of NIH Human Research Protections Program (HRPP) 
Policy 404 Research Involving NIH Staff as Subjects.
Consent from NIH staff for whom this research is taking place within their own work unit or is 
conducted by any of their supervisors will, when possible, be obtained by an individual in a non-
supervisory relationship with that staff member. Similarly, for family of the study team, a study 
team member unrelated to the participant will obtain their informed consent. When consent of 
that staff member or family member is conducted, a third party will be present to observe the 
consent process in order to minimize the risk of undue pressure on them.
10.2
STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the principal investigator, 
sponsor, and regulatory authorities. If the study is prematurely terminated or suspended, the 
principal investigator will promptly inform the study participants, IRB, sponsor, and FDA, as 
applicable, and will provide the reason(s) for the termination or suspension. Study participants 
will be informed of changes to the study visit schedule, if applicable.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

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
Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
In the case of a temporary suspension, the study may resume once concerns about safety, 
protocol compliance, and data quality are addressed and satisfy the sponsor, IRB, and FDA, as 
applicable.
10.3
CONFIDENTIALITY AND PRIVACY
All records will be kept confidential to the extent provided by federal, state, and local law. 
Authorized representatives of the NIAID may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records. Records will be 
kept locked and data will be coded. Any personally identifiable information maintained for this 
study will be kept on restricted-access computers and networks. Personally identifiable 
information will only be shared with individuals authorized to receive it under this protocol. 
Individuals not authorized to receive personally identifiable information will be provided with 
coded information only, as needed. Clinical information will not be released without written 
permission of the participant, except as necessary for monitoring by the IRB, NIAID, Office for 
Human Research Protections (OHRP), the FDA, or the sponsor’s designee.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the NIH. This certificate protects identifiable research information from forced 
disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, 
legislative, or other proceeding, whether at the federal, state, or local level. By protecting 
researchers and institutions from being compelled to disclose information that would identify 
research participants, Certificates of Confidentiality help achieve the research objectives and 
promote participation in studies by helping assure confidentiality and privacy to participants.
10.4
FUTURE USE OF STORED SPECIMENS AND DATA
Coded specimens and data will be stored at the NIH indefinitely for future research after the 
study is complete. Human genetic testing may be performed. Plans for future use of specimens 
and data will be described in the informed consent document. Specimens will be stored at the 
NIH Clinical Center in a locked facility with limited access. Data will be kept in password-
protected computers. Only investigators or their designees will have access to the code key.
Other investigators (at NIH and elsewhere) may wish to study these specimens and data. If the 
planned research falls within the category of “human subjects research” on the part of the 
investigators, NIH IRB review and approval will be obtained. This includes the investigators 
sending out coded and linked specimens or data and getting results that they can link back to 
their participants.
10.5
SAFETY OVERSIGHT
Safety oversight for this study is described in section 8.4.4.

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10.6
CLINICAL MONITORING
According to the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E6(R2) Good Clinical Practice (GCP) guidelines, section 
5.18, and FDA 21 CFR 312.50, clinical protocols are required to be adequately monitored by the 
study sponsor. This study monitoring will be conducted according to the “NIAID Intramural 
Clinical Monitoring Guidelines.” Monitors under contract to the NIAID/OCRPRO will visit the 
clinical research site to monitor aspects of the study in accordance with the appropriate 
regulations and the approved protocol. The objectives of a monitoring visit will be: 1) to verify 
the existence of signed informed consent documents and documentation of the consent process 
for each monitored participant; 2) to verify the prompt and accurate recording of all monitored 
data points in CRIMSON and prompt reporting of all SAEs; 3) to compare abstracted 
information entered into CRIMSON with individual participants’ records and source documents 
(participants’ charts, laboratory analyses and test results, physicians’ progress notes, nurses’ 
notes, and any other relevant original participant information); and 4) to help ensure investigators 
are in compliance with the protocol. The monitors also will inspect the clinical site regulatory 
files to ensure that regulatory requirements (Office for Human Research Protections [OHRP], 
FDA) and applicable guidelines (ICH GCP) are being followed. During the monitoring visits, the 
investigator (and/or designee) and other study personnel will be available to discuss the study 
progress and monitoring visit.
The investigator (and/or designee) will make study documents (e.g., consent forms, CRIMSON 
data abstracts) and pertinent hospital or clinical records, including CRIMSON, readily available 
for inspection by the local IRB, FDA, the site monitors, and the NIAID staff for confirmation of 
the study data.
A specific protocol monitoring plan will be discussed with the principal investigator and study 
staff prior to enrollment. The plan will outline the frequency of monitoring visits based on such 
factors as study enrollment, data collection status, and regulatory obligations.
10.7
QUALITY ASSURANCE AND QUALITY CONTROL
To help ensure that NIH Office of Research Support and Compliance procedures and Good 
Clinical Practices (GCP) are being carried out, a Clinical Trials Management designee within the 
Office of Clinical Research Policy and Regulatory Operations, Regulatory Compliance and 
Human Subjects Protection Program will conduct a study initiation visit before study enrollment 
begins. The purpose of this meeting is to review with the principal investigator and study team 
designees the roles and responsibilities concerning their commitment to adhere to the 
requirements of the protocol, especially in terms of NIH OHSRP reporting requirements for 
reportable events. In addition, the quality management and data management plan for the study 
will be reviewed.
10.8
DATA HANDLING AND RECORD KEEPING
10.8.1
Data Collection and Management Responsibilities
Study data will be maintained in REDCap, CRIMSON, and CRIS and collected directly from 
participants during study visits and telephone calls or will be abstracted from participants’ 
medical records. Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary to confirm the data abstracted for this study. Data 

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entry into CRIMSON will be performed by authorized individuals. The investigator is 
responsible for assuring that the data collected are complete, accurate, and recorded in a timely 
manner. Study data, including cumulative participant accrual numbers, should be generated via 
the chosen data capture method and submitted to study oversight bodies as needed.
10.8.2
Study Records Retention
Study documents will be retained in accordance with regulatory and institutional requirements, 
ICH GCP guidelines, and the NIH Intramural Records Retention Schedule. No records will be 
destroyed without the written consent of the principal investigator and sponsor, as applicable.
Should the investigator wish to assign the study records to another party and/or move them to 
another location, the investigator will provide written notification of such intent to 
OCRPRO/NIAID with the name of the person who will accept responsibility for the transferred 
records and/or their new location. Relocation of research records will not proceed without 
written permission from OCRPRO/NIAID.
10.9
PROTOCOL DEVIATIONS AND NON-COMPLIANCE
It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations and/or non-compliance to the NIH IRB as per Policy 801. All deviations must be 
addressed in study source documents and reported as specified in the protocol quality 
management plan and/or monitoring plan. The investigator is responsible for knowing and 
adhering to the reviewing IRB requirements.
10.9.1
NIH Definition of Protocol Deviation
The definition of a protocol deviation is provided in section 8.4.1.
10.10 REPORTING TO THE NIAID CLINICAL DIRECTOR 
The principal investigator will report UPs, major protocol deviations, and deaths to the NIAID 
clinical director according to institutional timelines.
10.11 PUBLICATION AND DATA SHARING POLICY
10.11.1
Human Data Sharing Plan
We will comply with NIH policies on data access, sharing, and dissemination, and clinical trials 
registration, as applicable. Results information from this trial will be submitted to 
ClinicalTrials.gov. Human data generated in this study may be shared for future research as 
follows:

De-identified data in an NIH-supported public data repository, such as the database of 
Genotypes and Phenotypes (dbGaP), the National Center for Biotechnology Information 
(NCBI) Gene Expression Omnibus (GEO), and the NCBI Sequence Read Archive 
(SRA).

De-identified data in another public repository.

Identified data in the Biomedical Translational Research Information System (BTRIS, 
automatic for activities in the Clinical Center). 

De-identified or identified data with approved outside collaborators under appropriate 
agreements.

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
De-identified data in publications and/or public presentations.
Data will be shared at the time of or shortly after publication.
10.11.2
Genomic Data Sharing Compliance
Although the NIH Genomic Data Sharing Policy is not required for this research, we may want 
to share genomic data with an NIH-supported repository, as described in the previous section. 
We will comply with all requirements in order to do so, including creating a Data Sharing Plan 
and completing an Institutional Certification and seeking approval prior to beginning the 
research. Prior to sharing the data, we will de-identify it, code it, and maintain the code key 
linked to the data.
10.12 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 
conduct of this trial. The study leadership in conjunction with NIAID has established policies 
and procedures for all study group members to disclose all conflicts of interest and will establish 
a mechanism for the management of all reported dualities of interest.

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11 ABBREVIATIONS
AE
Adverse Event
AR
Adverse Reaction
CAPA
Corrective and Preventive Action Plan
CARPA
Complement Activation Related Pseudoalleregy
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CLIA
Clinical Laboratory Improvement Amendments
CMP
Clinical Monitoring Plan
COC
Certificate of Confidentiality
CoFAR
Consortium for Food Allergy Research
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form
CSO
Clinical Safety Office
CTM
Clinical Trials Management
DLM
Department of Laboratory Medicine
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
ESI
Event of Special Interest
EUA
Emergency Use Authorization
FDA
Food and Drug Administration
FXII
Factor XII
GCP
Good Clinical Practice
HRPP
Human Research Protections Program
ICH
International Conference on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICU
Intensive Care Unit
IDCU
Investigational Drug Control Unit
IND
Investigational New Drug application
IRB
Institutional Review Board
MOP
Manual of Procedures
MRGPRX2
MAS-Related G Protein-Coupled Receptor-X2
NIH 
National Institutes of Health
OHRP
Office for Human Research Protections
PAF
Platelet Activating Factor
PAF-AH
Platelet Activating Factor Acetylhydrolase
PEG
Polyethylene Glycol
PI
Principal Investigator
PSEE
Protocol-Specified Exempt Event
REDCap
Research Electronic Data Capture
SAE
Serious Adverse Event
SAR
Suspected Adverse Reaction
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2

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SERF
Safety Expedited Report Form
SMM
Sponsor Medical Monitor
SNP
Single-Nucleotide Polymorphism
SOA
Schedule of Activities
SRCP
Safety Review and Communication Plan
SUSAR
Serious and Unexpected Suspected Adverse Reaction
UP
Unanticipated Problem
UPnonAE
Unanticipated Problem that is not an Adverse Event
US
United States
VAERS
Vaccine Adverse Event Reporting System

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Marc G, Moreira ED, Zerbini C et al: Safety and Efficacy of the BNT162b2 mRNA 
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Banerji A, Wickner PG, Saff R, Stone CA, Jr., Robinson LB, Long AA, Wolfson AR, 
Williams P, Khan DA, Phillips E et al: mRNA Vaccines to Prevent COVID-19 Disease 
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APPENDIX A. MODIFIED COFAR GRADING SCALE FOR SYSTEMIC ALLERGIC 
REACTIONS VERSION 3.0
Grade 1
Grade 2
Grade 3 1
Grade 4 1
Grade 5
Reaction involving one 
of the following organ 
systems in which the 
symptoms are mild: 
 
Cutaneous: Generalized 
pruritus, generalized 
urticaria, flushing, 
angioedema 
 
Upper respiratory: 
Rhinitis, cough unrelated 
to laryngeal edema or 
bronchospasm 
 
Conjunctival: 
Injection/redness, 
itching, tearing 
 
GI:  
Nausea, abdominal pain 
(no change in activity 
level), single episode of 
vomiting and/or single 
episode of diarrhea 
Reaction involving 2 or more 
of the following organ 
systems in which the 
symptoms are mild: 
 
Cutaneous: 
Generalized pruritus, generalized 
urticaria, flushing, angioedema 
 
Upper respiratory: 
Rhinitis, cough unrelated to 
laryngeal edema or 
bronchospasm 
 
Conjunctival: Injection/redness, 
itching, tearing 
 
GI: 
Nausea, abdominal pain (no 
change in activity level), single 
episode of vomiting, and/or 
single episode of diarrhea 
 
OR 
 
Reaction involving at least 
one of the following organ 
systems in which the 
symptoms are moderate: 
 
Cutaneous: 
Generalized pruritus, generalized 
urticaria, flushing, angioedema 
 
Upper respiratory: Rhinitis, 
cough unrelated to laryngeal 
edema or bronchospasm 
 
Conjunctival: 
Injection/redness, itching, 
tearing 
 
GI: 
Nausea, abdominal pain (with 
change in activity level), 2 
episodes of vomiting and/or 
diarrhea 
Reaction involving one 
or more of the following 
organ systems: 
 
Lower respiratory: 
Throat tightness, 
wheezing, chest 
tightness, dyspnea, cough 
that responds to 
treatment with or without 
supplemental oxygen 
 
GI: 
Severe abdominal pain, 
more than 2 episodes of 
vomiting and/or 
diarrhea 
Cardiovascular: 
Reduced BP without 
associated symptoms of 
end-organ dysfunction 
(e.g., hypotonia 
[collapse], syncope) 
defined as systolic BP 
of less than 90 mmHg 
or >30% decrease from 
baseline
Life-threatening reaction 
involving one or more of 
the following organ 
systems with or without 
other symptoms listed in 
Grades 1 to 3: 
 
Lower respiratory: Throat 
tightness with stridor, 
wheezing, chest tightness, 
dyspnea, or cough associated 
with a requirement for 
supplemental oxygen and 
refractoriness to short-acting 
bronchodilator treatment 
(including IM epinephrine) 
 
OR 
 
Respiratory compromise 
requiring mechanical 
support 
 
Cardiovascular: Reduced 
BP with associated 
symptoms of end-organ 
dysfunction (e.g., hypotonia 
[collapse], syncope) defined 
as: systolic BP of less than 
90 mmHg or >30% 
decrease from baseline 
 Death 
1 Patients treated with epinephrine infusion without documented hypoxia, hypotension, or evidence of end-organ damage would 
be considered as COFAR grade 3 allergic reaction and may be eligible per investigator discretion.

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APPENDIX B. BRIGHTON COLLABORATION CRITERIA
Case Definition of Anaphylaxis 
For all levels of 
diagnostic certainty
Level 1 of diagnostic 
certainty 
Level 2 of diagnostic certainty
Level 3 of diagnostic 
certainty
Anaphylaxis is a clinical 
syndrome characterized 
by sudden onset 
AND
rapid progression of signs 
and symptoms 
AND
involving multiple (≥2) 
organ systems
≥1 major dermatological 
AND 
≥1 major cardiovascular 
AND/OR
≥1 major respiratory 
criterion 
≥1 major cardiovascular AND ≥1 
major respiratory criterion 
OR 
≥1 major cardiovascular OR 
respiratory criterion 
AND 
≥1 minor criterion involving 
≥1 different system (other 
than cardiovascular or 
respiratory systems) 
OR 
(≥1 major dermatologic) 
AND (≥1 minor 
cardiovascular AND/OR 
minor respiratory criterion) 
≥1 minor cardiovascular 
OR respiratory criterion 
AND 
≥1 minor criterion from 
each of ≥2 different 
systems/ categories 
The case definition should be applied when there is no clear alternative diagnosis for the reported event to account for the combination of 
symptoms. 
 
Major and Minor Criteria Used in the Case Definition of Anaphylaxis  
 
Major Criteria 
Minor Criteria 
Dermatologic or 
mucosal 
• generalized urticaria (hives) or generalized erythema 
• angioedema*, localized or generalized 
• generalized pruritus with skin rash 
• generalized pruritus without skin rash 
• generalized prickle sensation 
• localized injection site urticaria 
• red and itchy eyes 
Cardiovascular 
• measured hypotension 
• clinical diagnosis of uncompensated shock, indicated 
by the combination of at least 3 of the following: 
-
tachycardia 
-
capillary refill time >3 s 
-
reduced central pulse volume 
-
decreased level of consciousness or loss of 
consciousness 
• reduced peripheral circulation as indicated by 
the combination of at least 2 of 
-
tachycardia 
-
a capillary refill time of >3 s without 
hypotension 
-
a decreased level of consciousness 
Respiratory 
• bilateral wheeze (bronchospasm) 
• stridor 
• upper airway swelling (lip, tongue, throat, uvula, or 
larynx) 
• respiratory distress—2 or more of the following: 
-
tachypnoea 
-
increased use of accessory respiratory 
muscles (sternocleidomastoid, intercostals, 
etc.) 
-
recession 
-
cyanosis 
-
grunting 
• persistent dry cough 
• hoarse voice 
• difficulty breathing without wheeze or stridor 
• sensation of throat closure 
• sneezing, rhinorrhea 
Gastrointestinal 
 
• diarrhoea 
• abdominal pain 
• nausea 
• vomiting 
Laboratory 
 
Mast cell tryptase elevation > upper normal limit 
* Not hereditary angioedema