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

NCT04761822 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: DAIT COVID-19-004NIAID CRMS ID#: 38814
• Study Type: interventional
• Target: 746
• Locations: 1 country
• Sites: 29

Brief Summary

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

Conditions

SARS-CoV Infection; COVID-19; Allergic Reaction; Mast Cell Disorder

Keywords

SARS-CoV-2 vaccination; COVID-19 vaccination; Systemic Allergic Reactions to SARS-CoV-2 vaccination

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (12)

• 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.

  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.

  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.

  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.

  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.

  Within the 90-minute post-vaccination observation period to the first dose of the Pfizer-BioNTech COVID-19 Vaccine.

Study Arms (4)

Moderna COVID-19 Vaccine

EXPERIMENTAL

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

Pfizer-BioNTech COVID-19 Vaccine

EXPERIMENTAL

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

Placebo +Moderna COVID-19 Vaccine

EXPERIMENTAL

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; Biological: Placebo

Placebo+Pfizer-BioNTech COVID-19 Vaccine

EXPERIMENTAL

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; Biological: Placebo

Interventions

Moderna COVID-19 Vaccine BIOLOGICAL

Intramuscular injection

Also known as: mRNA-1273

Moderna COVID-19 Vaccine; Placebo +Moderna COVID-19 Vaccine

Pfizer-BioNTech COVID-19 Vaccine BIOLOGICAL

Intramuscular injection

Also known as: BNT162b2

Pfizer-BioNTech COVID-19 Vaccine; Placebo+Pfizer-BioNTech COVID-19 Vaccine

Placebo BIOLOGICAL

Intramuscular injection

Also known as: sterile, preservative-free 0.9% Sodium Chloride Injection

Placebo +Moderna COVID-19 Vaccine; Placebo+Pfizer-BioNTech COVID-19 Vaccine

Eligibility Criteria

• Age: 5 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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):
• Able to understand and provide informed consent
• 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)
• 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
• 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:
• 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
• 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
• History of documented, immediate allergic reactions to 2 or more unrelated drugs within the last 15 years
• 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

You may not qualify if:

• Individuals who meet any of these criteria are not eligible for enrollment as study participants:
• 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
• Weight less than 15 kg (33 lbs)
• 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
• History of a severe reaction to any component of the Pfizer-BioNTech COVID-19 Vaccine or Moderna COVID-19 Vaccine
• History of contact dermatitis with confirmed patch test reaction to Prevalence of polyethylene glycol (PEG)
• History of reaction to Doxil®
• Known exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and still within the quarantine window
• 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
• 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
• History of autoimmune or other disorders requiring systemic immune modulators
• History of acute urticaria within 28 days of randomization
• Pregnant
• Have received any vaccines within 14 days of the first study vaccination/placebo administration or plan to receive other vaccines during the study period
• Had any allergen immunotherapy administration within 24 hours prior to vaccination/placebo administration or plan to receive within 24 hours after vaccination/placebo administration

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Immune Tolerance Network (ITN): collaborator
• Rho Federal Systems Division, Inc.: collaborator

Study Sites (29)

University of Arizona Health Sciences, College of Medicine Tucson, Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine

Tucson, Arizona, 85724, United States

Location

Arkansas Children's, University of Arkansas for Medical Sciences

Little Rock, Arkansas, 72202, United States

Location

University of California, Los Angeles Medical Center

Los Angeles, California, 90095, United States

Location

Stanford Medicine, Sean N. Parker Center for Allergy & Asthma Research

Stanford, California, 94040, United States

Location

National Jewish Health

Denver, Colorado, 80206, United States

Location

University Health, University of Miami Health System

Miami, Florida, 33136, United States

Location

University of South Florida Asthma Allergy and Immunology Clinical Research Unit

Tampa, Florida, 33613, United States

Location

Emory University School of Medicine, Emory Healthcare: Emory Clinic Allergy and Immunology

Atlanta, Georgia, 30324, United States

Location

Sinus and Allergy Center of Northwestern University

Chicago, Illinois, 60611, United States

Location

NorthShore University HealthSystem, Dermatology Clinical Trials Unit

Skokie, Illinois, 60077, United States

Location

University of Iowa Health Care

Iowa City, Iowa, 52242, United States

Location

Johns Hopkins Bayview Medical Center

Baltimore, Maryland, 21224, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Michigan Health

Ann Arbor, Michigan, 48109, United States

Location

Henry Ford Hospital and Health System

Detroit, Michigan, 48202, United States

Location

Saint Louis University Care Center for Specialized Medicine

St Louis, Missouri, 63104, United States

Location

Mount Sinai Hospital, Department of Medicine, Division of Clinical Immunology

New York, New York, 10029, United States

Location

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

Rochester Regional Health

Rochester, New York, 14607, United States

Location

North Carolina Translational and Clinical Sciences Institute-Clinical & Translational Research Center (CTRC) at the University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Cleveland Clinic, Allergy & Clinical Immunology

Cleveland, Ohio, 44195, United States

Location

Penn State Health Allergy, Milton S. Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Baylor College of Medicine Medical Center

Houston, Texas, 77030, United States

Location

University of Virginia Health System: Department of Medicine, Division of Allergy and Immunology

Charlottesville, Virginia, 22908, United States

Location

Virginia Commonwealth University, Department of Internal Medicine, Division of Rheumatology, Allergy & Immunology

Richmond, Virginia, 23298, United States

Location

University of Wisconsin Asthma Allergy Pulmonary Research

Madison, Wisconsin, 53792, United States

Location

Related Links

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

MeSH Terms

Conditions

Severe Acute Respiratory Syndrome; COVID-19; Hypersensitivity; Mastocytosis

Interventions

2019-nCoV Vaccine mRNA-1273; BNT162 Vaccine; Sodium Chloride

Condition Hierarchy (Ancestors)

Respiratory Tract Infections; Infections; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Immune System Diseases; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Mast Cell Activation Disorders

Intervention Hierarchy (Ancestors)

mRNA Vaccines; Nucleic Acid-Based Vaccines; Vaccines, Synthetic; Recombinant Proteins; Proteins; Amino Acids, Peptides, and Proteins; Vaccines; Biological Products; Complex Mixtures; COVID-19 Vaccines; Viral Vaccines; Antigens; Biological Factors; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• 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

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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 study participant which vaccine has been assigned, once their second injection is scheduled. Participants and the staff will be unblinded (unmasked) during the follow-up call 3 days after the second injection when a third appointment (for those who received a placebo injection first) is, or is not (active vaccinations only) scheduled.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 17, 2021
• First Posted: February 21, 2021
• Study Start: April 7, 2021
• Primary Completion: April 20, 2022
• Study Completion: April 27, 2022
• Last Updated: August 12, 2025
• Results First Posted: June 15, 2023

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Time Frame: After completion of the trial, within 24 months status post database lock.
• 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.

Locations

US (29)