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

NCT04977479 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 10000460000460-I
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Some people have allergic reactions to COVID-19 mRNA vaccines. Researchers want to learn more about these reactions to provide guidance on who can safely receive the vaccines, including a second dose in people who had a reaction to the first. Objective: To study the safety of giving a second mRNA COVID-19 vaccine dose to people who had a systemic allergic reaction to their first dose. Eligibility: People aged 16-69 who had a systemic allergic reaction to their first dose of COVID-19 vaccine. Design: Individuals who have underlying health issues may need to come to the NIH for screening tests to make sure they are safe to receive the vaccine. People who are eligible to participate in the study will be admitted to the NIH hospital and stay for at least 4 days. They will give urine samples. They will have a nasal swab SARS-CoV-2 test. They will have an intravenous line placed in each arm. They will get the study vaccine (Pfizer-BioNTech COVID-19 vaccine) and one dose of placebo on different days. They will have breathing tests. They may have clinical photography if they develop a rash. Participants will have 4 follow-up visits - 2 by phone and 2 in-person visits at the NIH campus . They will have allergy skin testing at one visit. Drops of different allergens or controls will be placed on their back or arm. The skin under each drop will be scratched with a tool. If the results are negative, a small amount of allergen will be injected just below the surface of their skin. Participants who have no or only a mild allergic reaction to the second dose of the vaccine may be eligible to receive a Booster dose at the NIH. Participation will last for approximately 5 months.

Conditions

Systemic Allergic Reaction

Keywords

polyethylene glycol (PEG); Pfizer-BioNTech COVID-19 vaccine; Moderna Covid-19 vaccine; Consortium for Food Allergy Research (CoFAR); SARS-CoV-2; Comirnaty

Outcome Measures

Primary Outcomes (2)

• Proportion of Participants Who Had Recurrent Systemic Allergic Reaction to Vaccine

  Proportion of participants who had recurrent systemic allergic reaction following active COVID-19 vaccine dose in this study. Allergic reactions were graded using Consortium of Food Allergy Research (CoFAR) grading scale (Version 3.0) where Grade 1 (mild) = mild symptoms involving one organ system (skin, conjunctiva, upper respiratory or gastrointestinal); Grade 2 (moderate) = mild symptoms involving ≥2 organ system (skin, conjunctiva, upper respiratory or gastrointestinal); Grade 3 (severe)= moderate to severe cardiovascular, lower respiratory or gastrointestinal symptoms, responsive to treatment and/or without end-organ dysfunction; Grade 4 = severe cardiovascular or lower respiratory symptoms, with end-organ dysfunction and/or refractory to treatment; and Grade 5 = death. Systemic allergic reaction was defined as CoFAR grade 1 reaction with elevated tryptase or CoFAR Grade ≥ 2 reaction irrespective of tryptase levels.

  Within the 3-hour post-vaccine observation period

• Proportion of Participants Who Had Recurrent Systemic Allergic Reaction to Vaccine

  Proportion of participants who had recurrent systemic allergic reaction following active COVID-19 vaccine dose in this study. Allergic reactions were graded using Consortium of Food Allergy Research (CoFAR) grading scale (Version 3.0) where Grade 1 (mild) = mild symptoms involving one organ system (skin, conjunctiva, upper respiratory or gastrointestinal); Grade 2 (moderate) = mild symptoms involving ≥2 organ system (skin, conjunctiva, upper respiratory or gastrointestinal); Grade 3 (severe)= moderate to severe cardiovascular, lower respiratory or gastrointestinal symptoms, responsive to treatment and/or without end-organ dysfunction; Grade 4 = severe cardiovascular or lower respiratory symptoms, with end-organ dysfunction and/or refractory to treatment; and Grade 5 = death. Systemic allergic reaction was defined as CoFAR grade 1 reaction with elevated tryptase or CoFAR Grade ≥ 2 reaction irrespective of tryptase levels.

  Within the 3-hour post-vaccine observation period

Secondary Outcomes (9)

• Proportion of Participants Who Developed Severe Systemic Allergic Reaction to Vaccine

  Within the 3-hour post-vaccine observation period

• Proportion of Participants Who Developed Mild or Moderate Systemic Allergic Reaction Following Active Vaccine Dose

  Within the 3-hour post-vaccine observation period

• Proportion of Participants Who Developed Mild or Moderate Systemic Allergic Reaction Following Active Vaccine Dose

  Within the 3-hour post-vaccine observation period

• Proportion of Participants Who Developed Anaphylactic Reaction Following Active Dose Delivered

  Within the 3-hour post-vaccine observation period

• Proportion of Participants Who Developed Anaphylactic Reaction Following Active Vaccine Dose

  Within the 3-hour post-vaccine observation period

Study Arms (3)

Blinded Active Vaccine 2

ACTIVE COMPARATOR

Participants who experienced a systemic allergic reaction after receiving their first full dose of the Pfizer-BioNTech or Moderna COVID-19 vaccine receives one dose of the active mRNA COVID-19 vaccine (0.3mL) intramuscularly followed by a wash out period of 24 hours then crossover to receive placebo (0.3 mL normal saline) intramuscularly.

Biological: Pfizer-BioNTech COVID-19 Vaccine (Comirnaty); Other: Placebo

Blinded Placebo

PLACEBO COMPARATOR

Participants who experienced a systemic allergic reaction after receiving their first full dose of the Pfizer-BioNTech or Moderna COVID-19 vaccine receives one dose of the placebo (0.3 mL normal saline) intramuscularly followed by a wash out period of 24 hours then crossover to receive the active mRNA COVID-19 vaccine (0.3mL) intramuscularly.

Biological: Pfizer-BioNTech COVID-19 Vaccine (Comirnaty); Other: Placebo

Open-Label Booster Vaccine

EXPERIMENTAL

Participants who did not suffer from a COFAR grade 3 or higher reaction after blinded active vaccine 2 were offered to receive booster dose of the active mRNA COVID-19 vaccine (0.3 mL) intramuscularly 5 months later.

Biological: Pfizer-BioNTech COVID-19 Vaccine (Comirnaty); Biological: Pfizer-BioNTech COVID-19 Vaccine, Bivalent

Interventions

Pfizer-BioNTech COVID-19 Vaccine (Comirnaty) BIOLOGICAL

mRNA vaccine for the prevention of COVID-19. Single dose (0.3mL) via IM.

Blinded Active Vaccine 2; Blinded Placebo; Open-Label Booster Vaccine

Placebo OTHER

Commercially available sterile, preservative-free 0.9% Sodium Chloride Injection, USP. Volume to match active vaccine controlling for and delivered as a single dose via IM.

Blinded Active Vaccine 2; Blinded Placebo

Pfizer-BioNTech COVID-19 Vaccine, Bivalent BIOLOGICAL

mRNA vaccine booster bivalent (Original and Omicron BA.4/BA.5) for the prevention of COVID-19. Single dose (0.3mL) via IM.

Open-Label Booster Vaccine

Eligibility Criteria

• Age: 16 Years - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• Ability to provide informed consent.
• Stated willingness to comply with all study procedures (including discontinuing medications as needed and availability for the duration of the study.
• Aged 16-69 years.
• 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.
• 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.
• Have a primary care physician or other health care provider who will manage their medical care outside of this study.

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• 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.
• Known exposure to SARS-CoV-2 and still within the quarantine window.
• 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
• Have an acute illness, including body temperature greater than 100.4 degrees F, within 14 days prior to enrollment.
• History of autoimmune or other disorders requiring systemic immune modulators.
• Are moderately or severely immunocompromised.
• History of acute urticaria within 28 days prior to enrollment.
• Pregnant.
• Have received any vaccines within 14 days prior to enrollment.
• Scheduled or planned receipt of approved or experimental vaccine prior to visit 3.
• 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.
• Have received a biological therapy within 6 months prior to enrollment.
• Use of systemic steroids for any reason within 28 days prior to enrollment.
• Use of zileuton within 14 days prior to enrollment.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Kee SA, Olivera A, Chatman L, Khalid MB, Li MJ, Chu E, Zektser E, Laky K, Frischmeyer-Guerrerio PA. Basophil activation test to BNT162b2 lacks specificity for predicting allergic reactions to the mRNA vaccine. J Allergy Clin Immunol Glob. 2025 May 13;4(3):100495. doi: 10.1016/j.jacig.2025.100495. eCollection 2025 Aug.

  PMID: 40497015 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

BNT162 Vaccine; BNT162b5

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; Vaccines, Combined

Limitations and Caveats

There was no pre-determined method for addressing causality of adverse events in the crossover phase of the study due to the brief washout period between the active vaccine and placebo administration.

Results Point of Contact

• Title: Pamela Frischmeyer-Guerrerio
• Organization: National Institute of Allergy and Infectious Diseases

pamela.guerrerio@nih.gov

301-402-9782

Study Officials

• Pamela A Guerrerio, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 24, 2021
• First Posted: July 27, 2021
• Study Start: September 8, 2021
• Primary Completion: June 17, 2022
• Study Completion: February 22, 2023
• Last Updated: October 16, 2023
• Results First Posted: October 16, 2023

Record last verified: 2023-01

Locations

US (1)