COVID19 SARS Vaccinations: Systemic Allergic Reactions to SARS-CoV-2 Vaccinations (SARS)

Systemic Allergic Reactions to SARS-CoV-2 Vaccination

Background: Allergic reactions have been reported to occur after vaccination with both the Pfizer-BioNTech COVID-19 Vaccine and Moderna COVID-19 Vaccine. Allergic reactions range from mild to severe and include life- threatening anaphylactic reactions, although no deaths have been reported with either vaccine.

This study is designed with two principal aims:

• To estimate the proportions of systemic allergic reactions to the Pfizer-BioNTech COVID-19 Vaccine and the Moderna COVID-19 Vaccine in a High-Allergy/Mast Cell Disorder (HA/MCD) population, and
• If the risk in the HA/MCD is demonstrable, to determine whether the proportions are higher in the HA/MCD in comparison to a representative population without severe allergies or mast cell disorders

Study Overview

• Status: Completed
• Conditions: COVID-19; SARS-CoV Infection; Allergic Reaction; Mast Cell Disorder
• Intervention / Treatment: Biological: Moderna COVID-19 Vaccine; Biological: Pfizer-BioNTech COVID-19 Vaccine; Biological: Placebo

Detailed Description

This is a multicenter, randomized, initially blinded (masked), phase 2 trial to assess SARS-CoV-2 vaccination reactions in two populations:

• One population including individuals with a history of allergic reactions or Mast Cell Disorder (HA/MCD), and
• One comparison population without severe allergies or mast cell disorders.

Approximately 2040 HA/MCD and 1360 comparison participants will be enrolled across participating sites in the United States. Approximately two-thirds of participants enrolled in each of the 2 groups will be female. This is because the vast majority of cases of anaphylaxis to the COVID-19 vaccines have occurred in women. Enrollment of participants who qualify only on the basis of reactions to multiple unrelated drugs will be limited to approximately 300.

Enrollment of the MCD group is anticipated to be at least 200 participants, and not more than 300 participants.

Participants in each population will be randomized 2:2:1:1 to receive the Pfizer-BioNTech COVID-19 Vaccine, Moderna COVID-19 Vaccine, placebo + Pfizer-BioNTech COVID-19 Vaccine, or placebo + Moderna COVID-19 Vaccine, if enrolled in the initial study period under protocol versions 1.0 -4.0. Participants enrolled under protocol version 5.0 will be randomized 2:1 to receive the Pfizer-BioNTech COVID-19 Vaccine or placebo + Pfizer-BioNTech COVID-19 Vaccine. If enrollment under protocol version 5.0 is robust and sustained, the active vaccine randomization may be changed to the Moderna COVID-19 Vaccine.

Participants randomized to one of the placebo groups will receive placebo as a first dose and will receive two doses of their assigned active vaccine at subsequent visits. During the first visit, all participants will be initially-blinded to whether they are receiving placebo or vaccine, and to which vaccine they are receiving (if enrolling under protocol versions 1.0 -4.0).

Due to the different dosing schedules for the Pfizer-BioNTech COVID-19 Vaccine and Moderna COVID-19 Vaccine, it will become apparent to both the site staff and the study participant which vaccine has been assigned, once the second injection visit is scheduled. However, the blind over placebo versus vaccine will remain in effect until after the second visit. During a follow-up call, scheduled 3 days after the second injection, participants will be unblinded as to whether they received placebo or active vaccine.

However under protocol version 5.0, participants will be told if they received placebo as the first injection during the following up conducted 3 days after. Participants in this phase of the study will also know which company's vaccine they are receiving, as the vaccines are anticipated to be used sequentially and will also be noted in the consent form.

Study Duration: Randomized and vaccinated participants will complete study participation in approximately 29 days if vaccinated with the Pfizer-BioNTech COVID-19 Vaccine, 36 days if vaccinated with the Moderna COVID-19 Vaccine. Participants enrolled under protocol versions 1.0 -4.0 will complete study participation in 50 or 64 days if administered placebo before receiving two doses of either the Pfizer-BioNTech COVID-19 Vaccine or the Moderna COVID-19 Vaccine, respectively and participants enrolled under protocol version 5.0 will complete participation in approximately 36 of 43 days, respectively, if they receive placebo first.

• Study Type: Interventional
• Enrollment (Actual): 746
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona Health Sciences, College of Medicine Tucson, Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's, University of Arkansas for Medical Sciences
  • California
    • Los Angeles, California, United States, 90095
      • University Of California, Los Angeles Medical Center
    • Stanford, California, United States, 94040
      • Stanford Medicine, Sean N. Parker Center for Allergy & Asthma Research
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • Florida
    • Miami, Florida, United States, 33136
      • University Health, University of Miami Health System
    • Tampa, Florida, United States, 33613
      • University of South Florida Asthma Allergy and Immunology Clinical Research Unit
  • Georgia
    • Atlanta, Georgia, United States, 30324
      • Emory University School of Medicine, Emory Healthcare: Emory Clinic Allergy and Immunology
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Sinus and Allergy Center of Northwestern University
    • Skokie, Illinois, United States, 60077
      • NorthShore University HealthSystem, Dermatology Clinical Trials Unit
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Health Care
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins Bayview Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital and Health System
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • Saint Louis University Care Center for Specialized Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Hospital, Department of Medicine, Division of Clinical Immunology
    • Rochester, New York, United States, 14607
      • Rochester Regional Health
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • North Carolina Translational and Clinical Sciences Institute-Clinical & Translational Research Center (CTRC) at the University of North Carolina at Chapel Hill
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic, Allergy & Clinical Immunology
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Health Allergy, Milton S. Hershey Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System: Department of Medicine, Division of Allergy and Immunology
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University, Department of Internal Medicine, Division of Rheumatology, Allergy & Immunology
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Asthma Allergy Pulmonary Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 17 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Individuals who meet all of the following criteria are eligible for enrollment as study participants:

Both groups (e.g., High-Allergy and Mast Cell Disorder (HA/MCD) Group and Comparison Group):

1. Able to understand and provide informed consent
2. Male or non-pregnant female ≥12 years of age on the date of first study vaccination/placebo administration (protocol versions 1.0 - 4.0) OR male or non-pregnant female 5-17 years of age on the date of first study vaccination/placebo administration (protocol version 5.0)

3. Females of childbearing potential must have a negative pregnancy test prior to the first vaccination and placebo administration, if applicable.

   --If a participant becomes pregnant after receiving a placebo dose but prior to receiving study vaccination, she will be discontinued from the study

4. Females of reproductive potential° and sexually active must agree to use FDA approved methods of birth control for the duration of the study. These include hormonal contraceptives, intrauterine device, double barrier contraception (i.e., condom plus diaphragm), or male partner with documented vasectomy.

   • Menopause is defined as at least 12 consecutive months without menses; if in question, a follicle stimulating hormone of ≥25 U/mL must be documented.
   • Hysterectomy, bilateral oophorectomy, or bilateral tubal ligation must be documented, as applicable; if documented, women with these conditions are not required to use additional contraception.

High-Allergy and Mast Cell Disorder (HA/MCD) Group:

Individuals who meet at least one of the following criteria are eligible for enrollment in the HA/MCD group:

1. History of a severe allergic reaction to food(s), allergen immunotherapy, insect venom(s), or latex with use of epinephrine within the last 15 years
2. History of an Emergency Department visit with convincing evidence of a systemic allergic reaction (consistent with CoFAR Grade 3 or higher) to food(s), allergen immunotherapy, insect venom(s), or latex within the last 15 years
3. History of documented, immediate allergic reactions to 2 or more unrelated drugs within the last 15 years
4. A convincing clinical history, or a history that is accompanied by a positive skin test, of an immediate reaction to a drug, vaccine, or latex within the last 15 years
5. History of physician-diagnosed idiopathic anaphylaxis requiring epinephrine or an Emergency Department visit in the last 15 years

6. History of a physician-diagnosed mast cell disorder (e.g., mastocytosis, mast cell activation syndrome [MCAS], or hereditary alpha-tryptasemia). MCAS must meet consensus criteria as defined below:

   • Criterion A: Typical clinical signs of severe, recurrent (episodic) systemic Mast Cell Activation are present (often in form of anaphylaxis)

     ---Definition of systemic: involving at least 2 organ systems

   • Criterion B: Involvement of Mast Cell (MC) is documented by biochemical studies

     --- Preferred marker: increase in serum tryptase level from the individual's baseline to plus 20% + 2 ng/ml

   • Criterion C: Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production or drugs blocking mediator release or effects of MC-derived mediators
   • NOTE: All 3 Mast Cell Activation Syndrome (MCAS) criteria (A + B + C) must be fulfilled to call a condition MCAS.

Comparison Group:

Individuals who meet all of the following criteria are eligible for enrollment in the comparison group:

1. No history of allergic asthma or atopic dermatitis within the last 10 years
2. No history of chronic spontaneous urticaria, or angioedema
3. No history of allergic reactions to foods or insect venoms
4. No history of allergic reactions to drugs or vaccines
5. No history of anaphylaxis
6. No history of a mast cell disorder (e.g., mastocytosis, mast cell activation syndrome [MCAS], or hereditary alpha- tryptasemia)

Exclusion Criteria:

Individuals who meet any of these criteria are not eligible for enrollment as study participants:

1. Inability or unwillingness of a participant and/or parent/legal guardian to give written informed consent and/or assent, as applicable, or to comply with study protocol
2. Weight less than 15 kg (33 lbs)
3. Prior receipt of any doses of the Pfizer-BioNTech coronavirus disease 2019 (COVID-19) Vaccine, Moderna COVID-19 Vaccine, or any other COVID-19 vaccine
4. History of a severe reaction to any component of the Pfizer-BioNTech COVID-19 Vaccine or Moderna COVID-19 Vaccine
5. History of contact dermatitis with confirmed patch test reaction to Prevalence of polyethylene glycol (PEG)
6. History of reaction to Doxil®
7. Known exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and still within the quarantine window
8. Symptoms consistent with acute COVID-19 infection or known COVID-19 infection (positive Polymerase chain reaction [PCR] or antigen test) and still within the quarantine window
9. Have an acute illness, including body temperature greater than 100.4 degrees Fahrenheit, within 14 days of the first study vaccination/placebo administration or 3 days prior to each subsequent vaccination
10. History of autoimmune or other disorders requiring systemic immune modulators
11. History of acute urticaria within 28 days of randomization
12. Pregnant
13. Have received any vaccines within 14 days of the first study vaccination/placebo administration or plan to receive other vaccines during the study period
14. Had any allergen immunotherapy administration within 24 hours prior to vaccination/placebo administration or plan to receive within 24 hours after vaccination/placebo administration
15. Have received a biologic therapy within 6 months of randomization
16. Use of systemic steroids for any reason within 28 days of randomization
17. Use of Zileuton® within 14 days of randomization
18. Use of any monoclonal antibody agent for treatment or prevention of COVID-19 within 3 months of randomization
19. Coronary artery disease, peripheral or cerebral vascular disease, unstable angina, or cardiac arrhythmia, other than supraventricular tachycardia (SVT)
20. Medically unstable hypertension
21. Current use of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, monoamine oxidase (MAO) inhibitors, tricyclic anti-depressants or other agents that could interfere with the treatment of anaphylaxis, in the opinion of the investigator
22. Unstable asthma within 3 months of randomization or symptomatic asthma on the day of vaccination, as assessed by the site investigator
23. Have past or current medical problems or findings from physical exam or laboratory testing not listed above, which in the opinion of the investigator, may pose additional risks from participation in the study or which may interfere with the ability to comply with study requirements --This includes individuals with underlying conditions or other medications that, in the opinion of the investigator, may increase risk in the event of an anaphylactic reaction or lead to complications following administration of epinephrine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Moderna COVID-19 Vaccine; The Moderna COVID-19 Vaccine (0.5 mL) will be administered intramuscularly in the deltoid, as a series of two doses (0.5 mL each) administered 1 month (28 days) apart.	Biological: Moderna COVID-19 Vaccine; Intramuscular injection; Other Names: mRNA-1273
Experimental: Pfizer-BioNTech COVID-19 Vaccine; The Pfizer-BioNTech COVID-19 Vaccine (0.3 mL) will be administered intramuscularly in the deltoid, as a series of two doses (0.3 mL each) administered 3 weeks (21 days) apart.	Biological: Pfizer-BioNTech COVID-19 Vaccine; Intramuscular injection; Other Names: BNT162b2
Experimental: Placebo +Moderna COVID-19 Vaccine; Participants will receive placebo as a first dose followed by two doses of their assigned active vaccine at subsequent visits. 0.5 mL of placebo will be administered intramuscularly in the deltoid. The placebo dose will be followed by two doses of Moderna COVID-19 Vaccine, with the first dose administered 1 month later. The Moderna COVID-19 Vaccine (0.5 mL) will be administered intramuscularly in the deltoid, as a series of two doses (0.5 mL each) administered 1 month (28 days) apart.	Biological: Moderna COVID-19 Vaccine; Intramuscular injection; Other Names: mRNA-1273; Biological: Placebo; Intramuscular injection; Other Names: sterile, preservative-free 0.9% Sodium Chloride Injection
Experimental: Placebo+Pfizer-BioNTech COVID-19 Vaccine; Participants will receive placebo as a first dose followed by two doses of their assigned active vaccine at subsequent visits. 0.3 mL of placebo will be administered intramuscularly in the deltoid. The placebo dose will be followed by two doses of Pfizer-BioNTech COVID-19 Vaccine, with the first dose administered 1 month later. The Pfizer-BioNTech COVID-19 Vaccine (0.3 mL) will be administered intramuscularly in the deltoid, as a series of two doses (0.3 mL each) administered 3 weeks (21 days) apart.	Biological: Pfizer-BioNTech COVID-19 Vaccine; Intramuscular injection; Other Names: BNT162b2; Biological: Placebo; Intramuscular injection; Other Names: sterile, preservative-free 0.9% Sodium Chloride Injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants Who Experienced a Systemic Allergic Reaction (CoFAR Grade 2+ Regardless of Tryptase or CoFAR Grade 1 With Elevated Tryptase) Within 90 Minutes Post-vaccination to Either Dose of Pfizer-BioNTech COVID-19 Vaccine.	Allergic reactions were graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale ranges from grade 1 through 5. The higher the grade, the more severe the allergic reaction. Tryptase is an enzyme released into the blood during an allergic reaction. An elevation in tryptase is defined as a value that is higher than 1.2 x the baseline tryptase plus 2 ng/ml. Subjects who did not receive their second dose of the vaccine were not included unless they reacted (per the endpoint) to the first dose. The comparison is between the High Allergy/Mast Cell Disorder and Comparison populations.	Within the 90-minute post-vaccination observation period to either dose of the Pfizer-BioNTech COVID-19 Vaccine.
Proportion of Participants Who Experienced a Systemic Allergic Reaction (CoFAR Grade 2+ Regardless of Tryptase or CoFAR Grade 1 With Elevated Tryptase) Within 90 Minutes Post-vaccination to Either Dose of the Moderna COVID-19 Vaccine.	Allergic reactions were graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale ranges from grade 1 through 5. The higher the grade, the more severe the allergic reaction. Tryptase is an enzyme released into the blood during an allergic reaction. An elevation in tryptase is defined as a value that is higher than 1.2 x the baseline tryptase plus 2 ng/ml. Subjects who did not receive their second dose of the vaccine were not included unless they reacted (per the endpoint) to the first dose. The comparison is between the High Allergy/Mast Cell Disorder and Comparison populations.	Within the 90-minute post-vaccination observation period to either dose of the Moderna COVID-19 Vaccine.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Proportion of Participants Who Experienced a Severe (CoFAR Grade 3+) Systemic Allergic Reaction Within 90 Minutes Post-vaccination to Either Dose of the Pfizer-BioNTech COVID-19 Vaccine.	Allergic reactions were graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale ranges from grade 1 through 5. The higher the grade, the more severe the allergic reaction. Subjects who did not receive their second dose of the vaccine were not included unless they reacted (per the endpoint) to the first dose. The comparison is between the High Allergy/Mast Cell Disorder and Comparison populations.	Within the 90-minute post-vaccination observation period to either dose of the Pfizer-BioNTech COVID-19 Vaccine.
The Proportion of Participants Who Experienced a Severe (CoFAR Grade 3+) Systemic Allergic Reaction Within the 90-minute Post-vaccination Observation Period to Either Dose of the Moderna COVID-19 Vaccine.	Allergic reactions were graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale ranges from grade 1 through 5. The higher the grade, the more severe the allergic reaction. Subjects who did not receive their second dose of the vaccine were not included unless they reacted (per the endpoint) to the first dose. The comparison is between the High Allergy/Mast Cell Disorder and Comparison populations.	Within the 90-minute post-vaccination observation period to either dose of the Moderna COVID-19 Vaccine.
The Proportion of Participants Who Experienced an Anaphylactic Reaction Per Brighton Collaboration Criteria (Levels 1-3) Within 90 Minutes Post-vaccination to Either Dose of the Pfizer-BioNTech COVID-19 Vaccine.	Allergic reactions were graded using the Brighton Collaboration Criteria. The scale ranges from level 1 through 3. Level 1 represents the highest level of diagnostic certainty that a reported case is anaphylaxis, levels 2 and 3 represent successively lower levels of diagnostic certainty. Subjects who did not receive their second dose of the vaccine were not included unless they reacted (per the endpoint) to the first dose. The comparison is between the High Allergy/Mast Cell Disorder and Comparison populations.	Within the 90-minute post-vaccination observation period to either dose of the Pfizer-BioNTech COVID-19 Vaccine.
The Proportion of Participants Who Experienced an Anaphylactic Reaction Per Brighton Collaboration Criteria (Levels 1-3) Within 90 Minutes Post-vaccination to Either Dose of the Moderna COVID-19 Vaccine.	Allergic reactions were graded using the Brighton Collaboration Criteria. The scale ranges from level 1 through 3. Level 1 represents the highest level of diagnostic certainty that a reported case is anaphylaxis, levels 2 and 3 represent successively lower levels of diagnostic certainty. Subjects who did not receive their second dose of the vaccine were not included unless they reacted (per the endpoint) to the first dose. The comparison is between the High Allergy/Mast Cell Disorder and Comparison populations.	Within the 90-minute post-vaccination observation period to either dose of the Moderna COVID-19 Vaccine.
Proportion of Participants Who Experienced a Systemic Allergic Reaction (CoFAR Grade 2+ Regardless of Tryptase or CoFAR Grade 1 With Elevated Tryptase) Within 90 Minutes Post-vaccination to the First Dose of the Pfizer-BioNTech COVID-19 Vaccine.	Allergic reactions were graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale ranges from grade 1 through 5. The higher the grade, the more severe the allergic reaction. Tryptase is an enzyme released into the blood during an allergic reaction. An elevation in tryptase is defined as a value that is higher than 1.2 x the baseline tryptase plus 2 ng/ml. The comparison is between the participants who received active vaccine as their first, fully blinded, injection (assigned to the Pfizer-BioNTech COVID-19 Vaccine arm) and participants who received their first active vaccine as their second injection (assigned to the Placebo + Pfizer-BioNTech COVID-19 Vaccine arm). Due to the design of the trial, participants would have understood that the second dose in any arm must be an active vaccination.	Within the 90-minute post-vaccination observation period to the first dose of the Pfizer-BioNTech COVID-19 Vaccine.
Proportion of Participants Who Experienced a Systemic Allergic Reaction (CoFAR Grade 2+ Regardless of Tryptase or CoFAR Grade 1 With Elevated Tryptase) Within 90 Minutes Post-vaccination to the First Dose of the Moderna COVID-19 Vaccine.	Allergic reactions were graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale ranges from grade 1 through 5. The higher the grade, the more severe the allergic reaction. Tryptase is an enzyme released into the blood during an allergic reaction. An elevation in tryptase is defined as a value that is higher than 1.2 x the baseline tryptase plus 2 ng/ml. The comparison is between the participants who received active vaccine as their first, fully blinded, injection (assigned to the Moderna COVID-19 Vaccine arm) and participants who received their first active vaccine as their second injection (assigned to the Placebo + Moderna COVID-19 Vaccine arm). Due to the design of the trial, participants would have understood that the second dose in any arm must be an active vaccination.	Within the 90-minute post-vaccination observation period to the first dose of the Moderna COVID-19 Vaccine.
Proportion of Participants Who Experienced a Systemic Allergic Reaction (CoFAR Grade 2+ Regardless of Tryptase or CoFAR Grade 1 With Elevated Tryptase) Within 90 Minutes Post-vaccination to the Second Dose of the Pfizer-BioNTech COVID-19 Vaccine.	Allergic reactions were graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale ranges from grade 1 through 5. The higher the grade, the more severe the allergic reaction. Tryptase is an enzyme released into the blood during an allergic reaction. An elevation in tryptase is defined as a value that is higher than 1.2 x the baseline tryptase plus 2 ng/ml. The comparison is between the participants who received the second active vaccine as their second injection (assigned to the Pfizer-BioNTech COVID-19 Vaccine arm) and participants who received the second active vaccine as their third injection (assigned to the Placebo + Pfizer-BioNTech COVID-19 Vaccine arm). This comparison is conditional on there being no systemic allergic reaction to the first dose.	Within the 90-minute post-vaccination observation period to the second dose of the Pfizer-BioNTech COVID-19 Vaccine.
Proportion of Participants Who Experienced a Systemic Allergic Reaction (CoFAR Grade 2+ Regardless of Tryptase or CoFAR Grade 1 With Elevated Tryptase) Within 90 Minutes Post-vaccination to the Second Dose of the Moderna COVID-19 Vaccine.	Allergic reactions were graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale is ranges from grade 1 through 5. The higher the grade, the more severe the allergic reaction. Tryptase is an enzyme released into the blood during an allergic reaction. An elevation in tryptase is defined as a value that is higher than 1.2 x the baseline tryptase plus 2 ng/ml. The comparison is between the participants who received the second active vaccine as their second injection (assigned to the Moderna COVID-19 Vaccine arm) and participants who received the second active vaccine as their third injection (assigned to the Placebo + Moderna COVID-19 Vaccine arm). This comparison is conditional on there being no systemic allergic reaction to the first dose.	Within the 90-minute post-vaccination observation period to the second dose of the Moderna COVID-19 Vaccine.
The Proportion of Participants Who Experienced a Systemic Allergic Reaction (CoFAR Grade 2+ Regardless of Tryptase or CoFAR Grade 1 With Elevated Tryptase) Within 90 Minutes Post-vaccination to the First Dose, Adjusting for Placebo.	Allergic reactions were graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale ranges from grade 1 through 5. The higher the grade, the more severe the allergic reaction. Tryptase is an enzyme released into the blood during an allergic reaction. An elevation in tryptase is defined as a value that is higher than 1.2 x the baseline tryptase plus 2 ng/ml. The comparison is between participants who had placebo as their first injection (either vaccine) and participants who had Pfizer-BioNTech COVID-19 Vaccine as their first injection. The comparison only includes subjects in the HA/MCD cohort.	Within the 90-minute post-vaccination observation period to the first injection (placebo or active).
The Proportion of Participants Who Experienced a Systemic Allergic Reaction (CoFAR Grade 2+ Regardless of Tryptase or CoFAR Grade 1 With Elevated Tryptase) Within 90 Minutes Post-vaccination to the First Dose, Adjusting for Placebo.	Allergic reactions were graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale is ranges from grade 1 through 5. The higher the grade, the more severe the allergic reaction. Tryptase is an enzyme released into the blood during an allergic reaction. An elevation in tryptase is defined as a value that is higher than 1.2 x the baseline tryptase plus 2 ng/ml. The comparison is between participants who had placebo as their first injection and participants who had Moderna COVID-19 Vaccine as their first injection. The comparison only includes subjects in the HA/MCD cohort.	Within the 90-minute post-vaccination observation period to the first injection.
The Proportion of Participants Who Experienced a Systemic Allergic Reaction (CoFAR Grade 2+) Within 48-hours Post-vaccination to Either Dose of the Pfizer-BioNTech COVID-19 Vaccine.	Allergic reactions were graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale ranges from grade 1 through 5. The higher the grade, the more severe the allergic reaction. Subjects who did not receive their second dose of the vaccine were not included unless they reacted (per the endpoint) to the first dose. The comparison is between the High Allergy/Mast Cell Disorder and Comparison populations.	After the 90 minute observation period to 48-hours post-vaccination to either dose of the Pfizer-BioNTech COVID-19 Vaccine.
The Proportion of Participants Who Experienced a Systemic Allergic Reaction (CoFAR Grade 2+) Within 48-hours Post-vaccination to Either Dose of the Moderna COVID-19 Vaccine.	Allergic reactions were graded using the Consortium of Food Allergy Research (CoFAR) Grading Scale for Systemic Allergic Reactions, Version 3.0. The scale ranges from grade 1 through 5. The higher the grade, the more severe the allergic reaction. Subjects who did not receive their second dose of the vaccine were not included unless they reacted (per the endpoint) to the first dose. The comparison is between the High Allergy/Mast Cell Disorder and Comparison populations.	After the 90 minute observation period to 48-hours post-vaccination to either dose of the Moderna COVID-19 Vaccine.

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Rho Federal Systems Division, Inc.; Immune Tolerance Network (ITN)
• Investigators: Study Chair: James R. Baker Jr., MD, Mary H. Weiser Food Allergy Center and Michigan Nanotechnology Institute for Medicine and the Biological Sciences; Study Chair: Rebecca S. Gruchalla, MD, PhD, Division of Allergy and Immunology Departments of Internal Medicine and Pediatrics, University of Texas Southwestern; Study Chair: N. Franklin Atkinson Jr., MD, Graduate Training Program in Clinical Investigation Associate TP Director, Allergy-Immunology Johns Hopkins Asthma & Allergy Center

Publications and helpful links

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)
• National Institutes of Health News Release Describing Study

Study record dates

Study Major Dates

• Study Start (Actual): April 7, 2021
• Primary Completion (Actual): April 20, 2022
• Study Completion (Actual): April 27, 2022

Study Registration Dates

• First Submitted: February 17, 2021
• First Submitted That Met QC Criteria: February 17, 2021
• First Posted (Actual): February 21, 2021

Study Record Updates

• Last Update Posted (Estimated): December 4, 2023
• Last Update Submitted That Met QC Criteria: November 30, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: COVID-19 vaccination; SARS-CoV-2 vaccination; Systemic Allergic Reactions to SARS-CoV-2 vaccination
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Severe Acute Respiratory Syndrome; COVID-19; Hypersensitivity; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: DAIT COVID-19-004; NIAID CRMS ID#: 38814 (Other Identifier: DAIT NIAID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Participant level data access and additional relevant materials will be made available upon completion of the trial.
• IPD Sharing Time Frame: After completion of the trial, within 24 months status post database lock.

IPD Sharing Access Criteria

Registration is available for the Immunology Database and Analysis Portal (ImmPort) at: https://www.immport.org/registration. Submit a rationale for the purpose of requesting study data access.

ImmPort is a long-term archive of clinical and mechanistic data, a National Institute of Allergy and Infectious Diseases Division of Allergy, Immunology and Transplantation (NIAID DAIT)-funded data repository. This archive is in support of the NIH mission to share data with the public. Data shared through ImmPort is provided by NIH-funded programs, other research organizations and individual scientists, ensuring these discoveries will be the foundation of future research.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No