## Protocol Section
### Identification Module
**NCT ID:** NCT04977479

**Brief Title:** 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

**Official 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

#### Organization Study ID Info
**ID:** 10000460
#### Organization
**Class:** NIH
**Full Name:** National Institutes of Health Clinical Center (CC)
#### Secondary ID Infos
**ID:** 000460-I
### Status Module
#### Completion Date
**Date:** 2023-02-22

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2023-10-16

**Type:** ACTUAL

**Last Update Submit Date:** 2023-09-21

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2022-06-17

**Type:** ACTUAL

#### Results First Post Date
**Date:** 2023-10-16

**Type:** ACTUAL

**Results First Submit Date:** 2023-06-16

**Results First Submit QC Date:** 2023-09-21

#### Start Date
**Date:** 2021-09-08

**Type:** ACTUAL

**Status Verified Date:** 2023-01

#### Study First Post Date
**Date:** 2021-07-27
**Type:** ACTUAL
**Study First Submit Date:** 2021-07-24
**Study First Submit QC Date:** 2021-07-24
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** NIH

**Name:** National Institute of Allergy and Infectious Diseases (NIAID)

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

### Description Module

**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.

**Detailed Description:** 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 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 \[1.2 X baseline plus 2ng/mL\]) 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.

Endpoints:\<TAB\>

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:

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 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.
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.

Exploratory Endpoints:

1. Prevalence of polyethylene glycol (PEG) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in each participant at baseline.
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.
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. 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.

### Conditions Module

**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

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** CROSSOVER

##### Masking Info

**Masking:** QUADRUPLE

**Who Masked:**

- PARTICIPANT

- CARE_PROVIDER

- INVESTIGATOR

- OUTCOMES_ASSESSOR

**Primary Purpose:** BASIC_SCIENCE

#### Enrollment Info

**Count:** 20

**Type:** ACTUAL

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** 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.

**Intervention Names:**

- Biological: Pfizer-BioNTech COVID-19 Vaccine (Comirnaty)

- Other: Placebo

**Label:** Blinded Active Vaccine 2

**Type:** ACTIVE_COMPARATOR

#### Arm Group 2

**Description:** 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.

**Intervention Names:**

- Biological: Pfizer-BioNTech COVID-19 Vaccine (Comirnaty)

- Other: Placebo

**Label:** Blinded Placebo

**Type:** PLACEBO_COMPARATOR

#### Arm Group 3

**Description:** 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.

**Intervention Names:**

- Biological: Pfizer-BioNTech COVID-19 Vaccine (Comirnaty)

- Biological: Pfizer-BioNTech COVID-19 Vaccine, Bivalent

**Label:** Open-Label Booster Vaccine

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Blinded Active Vaccine 2

- Blinded Placebo

- Open-Label Booster Vaccine

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

**Name:** Pfizer-BioNTech COVID-19 Vaccine (Comirnaty)

**Type:** BIOLOGICAL

#### Intervention 2

**Arm Group Labels:**

- Blinded Active Vaccine 2

- Blinded Placebo

**Description:** 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.

**Name:** Placebo

**Type:** OTHER

#### Intervention 3

**Arm Group Labels:**

- Open-Label Booster Vaccine

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

**Name:** Pfizer-BioNTech COVID-19 Vaccine, Bivalent

**Type:** BIOLOGICAL

### Outcomes Module

#### Primary Outcomes

**Description:** 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.

**Measure:** Proportion of Participants Who Had Recurrent Systemic Allergic Reaction to Vaccine

**Time Frame:** Within the 3-hour post-vaccine observation period

**Description:** 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.

**Measure:** Proportion of Participants Who Had Recurrent Systemic Allergic Reaction to Vaccine

**Time Frame:** Within the 3-hour post-vaccine observation period

#### Secondary Outcomes

**Description:** Proportion of participants who developed severe 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.

Severe systemic allergic reaction was defined as CoFAR Grade ≥ 3 reaction, regardless of tryptase levels.

**Measure:** Proportion of Participants Who Developed Severe Systemic Allergic Reaction to Vaccine

**Time Frame:** Within the 3-hour post-vaccine observation period

**Description:** Proportion of participants who developed mild or moderate 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

Mild to moderate systemic allergic reaction was defined as CoFAR Grade 1 or 2 regardless of tryptase level.

**Measure:** Proportion of Participants Who Developed Mild or Moderate Systemic Allergic Reaction Following Active Vaccine Dose

**Time Frame:** Within the 3-hour post-vaccine observation period

**Description:** 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 tr

**Measure:** Proportion of Participants Who Developed Mild or Moderate Systemic Allergic Reaction Following Active Vaccine Dose

**Time Frame:** Within the 3-hour post-vaccine observation period

**Description:** Proportion of participants with anaphylactic reactions (Levels 1-3) per Brighton Collaboration Criteria to the COVID-19 vaccine after previously demonstrating a systemic allergic reaction to their first full dose of the COVID-19 vaccine. Anaphylaxis was defined using the Brighton Collaboration Criteria as a clinical syndrome characterized by a sudden onset and rapid progression of signs and symptoms involving ≥2 organ systems including skin, cardiovascular, respiratory, gastrointestinal or tryptase elevation (\>upper normal limit). Only specific clinical features from these organ systems meet major and/or minor criteria to provide level of diagnostic certainty for anaphylactic reaction. Reaction meeting levels 1-3 diagnostic certainty are consistent with anaphylaxis

**Measure:** Proportion of Participants Who Developed Anaphylactic Reaction Following Active Dose Delivered

**Time Frame:** Within the 3-hour post-vaccine observation period

**Description:** Proportion of participants with anaphylactic reactions (Levels 1-3) per Brighton Collaboration Criteria to the COVID-19 vaccine after previously demonstrating a systemic allergic reaction to their first full dose of the COVID-19 vaccine. Anaphylaxis was defined using the Brighton Collaboration Criteria as a clinical syndrome characterized by a sudden onset and rapid progression of signs and symptoms involving ≥2 organ systems including skin, cardiovascular, respiratory, gastrointestinal or tryptase elevation (\>upper normal limit). Only specific clinical features from these organ systems meet major and/or minor criteria to provide level of diagnostic certainty for anaphylactic reaction. Reaction meeting levels 1-3 diagnostic certainty are consistent with anaphylaxis.

**Measure:** Proportion of Participants Who Developed Anaphylactic Reaction Following Active Vaccine Dose

**Time Frame:** Within the 3-hour post-vaccine observation period

**Description:** Participants with recurrent systemic allergic reaction following active vaccine dose in this study compared with reaction in placebo. 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 level. Outcome was calculated as risk difference estimation.

**Measure:** Proportion of Participants Who Had Recurrent Systemic Allergic Reaction Following Active Vaccine Dose Compared With Rate of Reaction in Placebo

**Time Frame:** Within the 3-hour post-vaccine observation period

**Description:** Proportion of participants with less severe allergic reaction to the vaccine dose in this study than recorded reaction to the first full COVID-19 vaccine dose (pre-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.

**Measure:** Proportion of Participants With Less Severe Allergic Reaction to the Vaccine Dose Delivered in This Study Than Recorded Reaction to the First Full COVID-19 Vaccine Dose

**Time Frame:** Within the 3-hour post-vaccine observation period

**Description:** "Proportion of participants with more severe allergic reaction to the vaccine dose in this study than recorded reaction to the first full COVID-19 vaccine dose (pre-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.

**Measure:** Proportion of Participants With More Severe Systemic Allergic Reaction to the Vaccine Dose Delivered in This Study Than Recorded Reaction to the First Full Vaccine Dose

**Time Frame:** Within the 3-hour post-vaccine observation period

**Description:** "Proportion of participants with more severe allergic reaction to the vaccine dose in this study than recorded reaction to the first full COVID-19 vaccine dose (pre-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.

**Measure:** Proportion of Participants With More Severe Systemic Allergic Reaction to the Vaccine Dose Delivered in This Study Than Recorded Reaction to the First Full Vaccine Dose

**Time Frame:** Within the 3-hour post-vaccine observation period

### Eligibility Module

**Eligibility Criteria:** * INCLUSION CRITERIA:

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.

EXCLUSION CRITERIA:

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.
* 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.
* 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.

**Maximum Age:** 69 Years

**Minimum Age:** 16 Years

**Sex:** ALL

**Standard Ages:**

- CHILD

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Bethesda

**Country:** United States

**Facility:** National Institutes of Health Clinical Center

**State:** Maryland

**Zip:** 20892

#### Overall Officials

**Official 1:**

**Affiliation:** National Institute of Allergy and Infectious Diseases (NIAID)

**Name:** Pamela A Guerrerio, M.D.

**Role:** PRINCIPAL_INVESTIGATOR

### References Module

#### See Also Links

**Label:** NIH Clinical Center Detailed Web Page

**URL:** https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_000460-I.html

## Document Section

### Large Document Module

#### Large Docs

- Date: 2022-10-19

- Filename: Prot_SAP_000.pdf

- Has ICF: False

- Has Protocol: True

- Has SAP: True

- Label: Study Protocol and Statistical Analysis Plan

- Size: 449133

- Type Abbrev: Prot_SAP

- Upload Date: 2023-06-07T12:03

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000011024

- Term: Pneumonia, Viral

- ID: D000011014

- Term: Pneumonia

- ID: D000012141

- Term: Respiratory Tract Infections

- ID: D000007239

- Term: Infections

- ID: D000014777

- Term: Virus Diseases

- ID: D000018352

- Term: Coronavirus Infections

- ID: D000003333

- Term: Coronaviridae Infections

- ID: D000030341

- Term: Nidovirales Infections

- ID: D000012327

- Term: RNA Virus Infections

- ID: D000008171

- Term: Lung Diseases

- ID: D000012140

- Term: Respiratory Tract Diseases

- ID: D000007154

- Term: Immune System Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC01

- Name: Infections

- Abbrev: BC08

- Name: Respiratory Tract (Lung and Bronchial) Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC20

- Name: Immune System Diseases

- Abbrev: BC23

- Name: Symptoms and General Pathology

### Condition Browse Module - Browse Leaves

- ID: M2561

- Name: COVID-19

- Relevance: HIGH

- As Found: COVID-19

- ID: M10018

- Name: Hypersensitivity

- Relevance: HIGH

- As Found: Allergic Reaction

- ID: M8636

- Name: Food Hypersensitivity

- Relevance: LOW

- As Found: Unknown

- ID: M13904

- Name: Pneumonia

- Relevance: LOW

- As Found: Unknown

- ID: M13914

- Name: Pneumonia, Viral

- Relevance: LOW

- As Found: Unknown

- ID: M10283

- Name: Infections

- Relevance: LOW

- As Found: Unknown

- ID: M6368

- Name: Communicable Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M14978

- Name: Respiratory Tract Infections

- Relevance: LOW

- As Found: Unknown

- ID: M17522

- Name: Virus Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M20490

- Name: Coronavirus Infections

- Relevance: LOW

- As Found: Unknown

- ID: M6555

- Name: Coronaviridae Infections

- Relevance: LOW

- As Found: Unknown

- ID: M23685

- Name: Nidovirales Infections

- Relevance: LOW

- As Found: Unknown

- ID: M15149

- Name: RNA Virus Infections

- Relevance: LOW

- As Found: Unknown

- ID: M11168

- Name: Lung Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M14977

- Name: Respiratory Tract Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10200

- Name: Immune System Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000086382

- Term: COVID-19

- ID: D000006967

- Term: Hypersensitivity

### Intervention Browse Module - Ancestors

- ID: D000007155

- Term: Immunologic Factors

- ID: D000045505

- Term: Physiological Effects of Drugs

### Intervention Browse Module - Browse Branches

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M17360

- Name: Vaccines

- Relevance: HIGH

- As Found: Other

- ID: M10201

- Name: Immunologic Factors

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000014612

- Term: Vaccines

### Misc Info Module

#### Submission Tracking

##### First MCP Info

###### Post Date

- Date: 2023-07-12

- Type: ACTUAL

- Version Holder: 2024-05-24

## Results Section

### Adverse Events Module

**Description:** Adverse events associated with the crossover phase have been grouped under 'Overall Study' due to the brief washout period between the active vaccine and the placebo.

#### Event Groups

**Group ID:** EG000

**Title:** Blinded Active Vaccine 2

**Deaths Num At Risk:** 16

**Description:** 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

**ID:** EG000

**Other Num Affected:** 3

**Other Num at Risk:** 16

**Serious Number At Risk:** 16

**Title:** Blinded Active Vaccine 2

**Group ID:** EG001

**Title:** Placebo

**Deaths Num At Risk:** 16

**Description:** 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 placebo (0.3 mL normal saline) intramuscularly.

**ID:** EG001

**Other Num at Risk:** 16

**Serious Number At Risk:** 16

**Title:** Placebo

**Group ID:** EG002

**Title:** Open-Label Booster Vaccine

**Deaths Num At Risk:** 16

**Description:** 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.

**ID:** EG002

**Other Num Affected:** 16

**Other Num at Risk:** 16

**Serious Number At Risk:** 16

**Title:** Open-Label Booster Vaccine

**Group ID:** EG003

**Title:** Overall Study

**Deaths Num At Risk:** 16

**Description:** 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 or placebo (0.3 mL normal saline) intramuscularly in the crossover phase of study.

**ID:** EG003

**Other Num Affected:** 16

**Other Num at Risk:** 16

**Serious Number At Risk:** 16

**Title:** Overall Study

**Frequency Threshold:** 0

#### Other Events

**Term:** Anaemia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Blood and lymphatic system disorders

**Source Vocabulary:** 

**Term:** Eosinophilia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Blood and lymphatic system disorders

**Source Vocabulary:** 

**Term:** Leukocytosis

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Blood and lymphatic system disorders

**Source Vocabulary:** 

**Term:** Neutrophilia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Blood and lymphatic system disorders

**Source Vocabulary:** 

**Term:** Thrombocytosis

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Blood and lymphatic system disorders

**Source Vocabulary:** 

**Term:** Palpitations

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Cardiac disorders

**Source Vocabulary:** 

**Term:** Sinus tachycardia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Cardiac disorders

**Source Vocabulary:** 

**Term:** Tachycardia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Cardiac disorders

**Source Vocabulary:** 

**Term:** Eustachian tube dysfunction

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Ear and labyrinth disorders

**Source Vocabulary:** 

**Term:** Tinnitus

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Ear and labyrinth disorders

**Source Vocabulary:** 

**Term:** Eye irritation

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Eye disorders

**Source Vocabulary:** 

**Term:** Lacrimation increased

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Eye disorders

**Source Vocabulary:** 

**Term:** Vision blurred

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Eye disorders

**Source Vocabulary:** 

**Term:** Abdominal distension

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Gastrointestinal disorders

**Source Vocabulary:** 

**Term:** Abdominal hernia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Gastrointestinal disorders

**Source Vocabulary:** 

**Term:** Abdominal pain

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Gastrointestinal disorders

**Source Vocabulary:** 

**Term:** Abdominal pain upper

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Gastrointestinal disorders

**Source Vocabulary:** 

**Term:** Dry mouth

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Gastrointestinal disorders

**Source Vocabulary:** 

**Term:** Dysphagia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Gastrointestinal disorders

**Source Vocabulary:** 

**Term:** Nausea

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Gastrointestinal disorders

**Source Vocabulary:** 

**Term:** Proctitis

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Gastrointestinal disorders

**Source Vocabulary:** 

**Term:** Toothache

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Gastrointestinal disorders

**Source Vocabulary:** 

**Term:** Vomiting

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Gastrointestinal disorders

**Source Vocabulary:** 

**Term:** Application site pruritus

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Chest discomfort

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Chest pain

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Chills

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Discomfort

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Facial pain

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Fatigue

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Feeling abnormal

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Feeling hot

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Gait disturbance

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Injection site erythema

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Injection site induration

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Injection site oedema

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Injection site pain

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Injection site pruritus

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Injection site reaction

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Injection site warmth

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Non-cardiac chest pain

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Pyrexia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Tenderness

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Vessel puncture site bruise

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** General disorders

**Source Vocabulary:** 

**Term:** Anaphylactic reaction

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Immune system disorders

**Source Vocabulary:** 

**Term:** Food allergy

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Immune system disorders

**Source Vocabulary:** 

**Term:** Hypersensitivity

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Immune system disorders

**Source Vocabulary:** 

**Term:** Body tinea

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Infections and infestations

**Source Vocabulary:** 

**Term:** Bronchitis

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Infections and infestations

**Source Vocabulary:** 

**Term:** Corona virus infection

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Infections and infestations

**Source Vocabulary:** 

**Term:** Gastroenteritis

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Infections and infestations

**Source Vocabulary:** 

**Term:** Otitis externa

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Infections and infestations

**Source Vocabulary:** 

**Term:** Pneumonia viral

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Infections and infestations

**Source Vocabulary:** 

**Term:** Upper respiratory tract infection

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Infections and infestations

**Source Vocabulary:** 

**Term:** Viral infection

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Infections and infestations

**Source Vocabulary:** 

**Term:** Vulvovaginal candidiasis

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Infections and infestations

**Source Vocabulary:** 

**Term:** Contusion

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Injury, poisoning and procedural complications

**Source Vocabulary:** 

**Term:** Exposure to communicable disease

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Injury, poisoning and procedural complications

**Source Vocabulary:** 

**Term:** Injury

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Injury, poisoning and procedural complications

**Source Vocabulary:** 

**Term:** Ligament sprain

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Injury, poisoning and procedural complications

**Source Vocabulary:** 

**Term:** Blood pressure increased

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Investigations

**Source Vocabulary:** 

**Term:** Eosinophil count increased

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Investigations

**Source Vocabulary:** 

**Term:** Lymphocyte count decreased

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Investigations

**Source Vocabulary:** 

**Term:** Lymphocyte count increased

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Investigations

**Source Vocabulary:** 

**Term:** Neutrophil count decreased

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Investigations

**Source Vocabulary:** 

**Term:** Neutrophil count increased

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Investigations

**Source Vocabulary:** 

**Term:** Platelet count decreased

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Investigations

**Source Vocabulary:** 

**Term:** White blood cell count decreased

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Investigations

**Source Vocabulary:** 

**Term:** White blood cell count increased

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Investigations

**Source Vocabulary:** 

**Term:** Decreased appetite

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Metabolism and nutrition disorders

**Source Vocabulary:** 

**Term:** Hypoglycaemia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Metabolism and nutrition disorders

**Source Vocabulary:** 

**Term:** Polydipsia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Metabolism and nutrition disorders

**Source Vocabulary:** 

**Term:** Arthralgia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Musculoskeletal and connective tissue disorders

**Source Vocabulary:** 

**Term:** Arthritis

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Musculoskeletal and connective tissue disorders

**Source Vocabulary:** 

**Term:** Back pain

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Musculoskeletal and connective tissue disorders

**Source Vocabulary:** 

**Term:** Musculoskeletal chest pain

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Musculoskeletal and connective tissue disorders

**Source Vocabulary:** 

**Term:** Myalgia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Musculoskeletal and connective tissue disorders

**Source Vocabulary:** 

**Term:** Pain in extremity

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Musculoskeletal and connective tissue disorders

**Source Vocabulary:** 

**Term:** Disturbance in attention

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Nervous system disorders

**Source Vocabulary:** 

**Term:** Dizziness

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Nervous system disorders

**Source Vocabulary:** 

**Term:** Dysgeusia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Nervous system disorders

**Source Vocabulary:** 

**Term:** Headache

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Nervous system disorders

**Source Vocabulary:** 

**Term:** Hypoaesthesia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Nervous system disorders

**Source Vocabulary:** 

**Term:** Migraine

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Nervous system disorders

**Source Vocabulary:** 

**Term:** Nerve compression

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Nervous system disorders

**Source Vocabulary:** 

**Term:** Paraesthesia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Nervous system disorders

**Source Vocabulary:** 

**Term:** Parosmia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Nervous system disorders

**Source Vocabulary:** 

**Term:** Presyncope

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Nervous system disorders

**Source Vocabulary:** 

**Term:** Taste disorder

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Nervous system disorders

**Source Vocabulary:** 

**Term:** Restlessness

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Psychiatric disorders

**Source Vocabulary:** 

**Term:** Micturition urgency

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Renal and urinary disorders

**Source Vocabulary:** 

**Term:** Intermenstrual bleeding

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Reproductive system and breast disorders

**Source Vocabulary:** 

**Term:** Menstruation irregular

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Reproductive system and breast disorders

**Source Vocabulary:** 

**Term:** Pelvic pain

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Reproductive system and breast disorders

**Source Vocabulary:** 

**Term:** Cough

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Respiratory, thoracic and mediastinal disorders

**Source Vocabulary:** 

**Term:** Dysphonia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Respiratory, thoracic and mediastinal disorders

**Source Vocabulary:** 

**Term:** Dyspnoea

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Respiratory, thoracic and mediastinal disorders

**Source Vocabulary:** 

**Term:** Nasal congestion

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Respiratory, thoracic and mediastinal disorders

**Source Vocabulary:** 

**Term:** Nasal discomfort

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Respiratory, thoracic and mediastinal disorders

**Source Vocabulary:** 

**Term:** Oropharyngeal pain

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Respiratory, thoracic and mediastinal disorders

**Source Vocabulary:** 

**Term:** Rhinorrhoea

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Respiratory, thoracic and mediastinal disorders

**Source Vocabulary:** 

**Term:** Sneezing

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Respiratory, thoracic and mediastinal disorders

**Source Vocabulary:** 

**Term:** Throat irritation

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Respiratory, thoracic and mediastinal disorders

**Source Vocabulary:** 

**Term:** Throat tightness

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Respiratory, thoracic and mediastinal disorders

**Source Vocabulary:** 

**Term:** Upper-airway cough syndrome

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Respiratory, thoracic and mediastinal disorders

**Source Vocabulary:** 

**Term:** Wheezing

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Respiratory, thoracic and mediastinal disorders

**Source Vocabulary:** 

**Term:** Ecchymosis

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Skin and subcutaneous tissue disorders

**Source Vocabulary:** 

**Term:** Erythema

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Skin and subcutaneous tissue disorders

**Source Vocabulary:** 

**Term:** Mechanical urticaria

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Skin and subcutaneous tissue disorders

**Source Vocabulary:** 

**Term:** Night sweats

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Skin and subcutaneous tissue disorders

**Source Vocabulary:** 

**Term:** Pruritus

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Skin and subcutaneous tissue disorders

**Source Vocabulary:** 

**Term:** Rash

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Skin and subcutaneous tissue disorders

**Source Vocabulary:** 

**Term:** Rash pruritic

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Skin and subcutaneous tissue disorders

**Source Vocabulary:** 

**Term:** Skin burning sensation

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Skin and subcutaneous tissue disorders

**Source Vocabulary:** 

**Term:** Bereavement

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Social circumstances

**Source Vocabulary:** 

**Term:** Catheter management

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Surgical and medical procedures

**Source Vocabulary:** 

**Term:** Flushing

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Vascular disorders

**Source Vocabulary:** 

**Term:** Haematoma

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Vascular disorders

**Source Vocabulary:** 

**Term:** Hypertension

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Vascular disorders

**Source Vocabulary:** 

**Term:** Hypotension

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Organ System:** Vascular disorders

**Source Vocabulary:** 

**Time Frame:** Blinded Active Vaccine 2 & Placebo - Within 3-hour post-vaccination Overall Study - up to 17 months post intervention in the crossover phase Open-Label Booster Vaccine - up to 11 months post vaccine administration

## Results Section - Baseline Characteristics Module

### Denomination Counts

**Group ID:** BG000

**Value:** 8

**Group ID:** BG001

**Value:** 8

**Group ID:** BG002

**Value:** 16

**Units:** Participants

### Group

**ID:** BG000

**Title:** Blinded Active Vaccine 2

**Description:** 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.

### Group

**ID:** BG001

**Title:** Blinded Placebo

**Description:** 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.

### Group

**ID:** BG002

**Title:** Total

**Description:** Total of all reporting groups

### Measure

#### Measurement

**Group ID:** BG000

**Value:** 0

#### Measurement

**Group ID:** BG001

**Value:** 0

#### Measurement

**Group ID:** BG002

**Value:** 0

**Category Title:** <=18 years

#### Measurement

**Group ID:** BG000

**Value:** 8

#### Measurement

**Group ID:** BG001

**Value:** 7

#### Measurement

**Group ID:** BG002

**Value:** 15

**Category Title:** Between 18 and 65 years

#### Measurement

**Group ID:** BG000

**Value:** 0

#### Measurement

**Group ID:** BG001

**Value:** 1

#### Measurement

**Group ID:** BG002

**Value:** 1

**Category Title:** >=65 years

**Class Title:** 

### Measure

#### Measurement

**Group ID:** BG000

**Value:** 8

#### Measurement

**Group ID:** BG001

**Value:** 7

#### Measurement

**Group ID:** BG002

**Value:** 15

**Category Title:** Female

#### Measurement

**Group ID:** BG000

**Value:** 0

#### Measurement

**Group ID:** BG001

**Value:** 1

#### Measurement

**Group ID:** BG002

**Value:** 1

**Category Title:** Male

**Class Title:** 

### Measure

#### Measurement

**Group ID:** BG000

**Value:** 2

#### Measurement

**Group ID:** BG001

**Value:** 3

#### Measurement

**Group ID:** BG002

**Value:** 5

**Category Title:** Hispanic or Latino

#### Measurement

**Group ID:** BG000

**Value:** 6

#### Measurement

**Group ID:** BG001

**Value:** 5

#### Measurement

**Group ID:** BG002

**Value:** 11

**Category Title:** Not Hispanic or Latino

#### Measurement

**Group ID:** BG000

**Value:** 0

#### Measurement

**Group ID:** BG001

**Value:** 0

#### Measurement

**Group ID:** BG002

**Value:** 0

**Category Title:** Unknown or Not Reported

**Class Title:** 

### Measure

#### Measurement

**Group ID:** BG000

**Value:** 0

#### Measurement

**Group ID:** BG001

**Value:** 0

#### Measurement

**Group ID:** BG002

**Value:** 0

**Category Title:** American Indian or Alaska Native

#### Measurement

**Group ID:** BG000

**Value:** 2

#### Measurement

**Group ID:** BG001

**Value:** 0

#### Measurement

**Group ID:** BG002

**Value:** 2

**Category Title:** Asian

#### Measurement

**Group ID:** BG000

**Value:** 0

#### Measurement

**Group ID:** BG001

**Value:** 0

#### Measurement

**Group ID:** BG002

**Value:** 0

**Category Title:** Native Hawaiian or Other Pacific Islander

#### Measurement

**Group ID:** BG000

**Value:** 1

#### Measurement

**Group ID:** BG001

**Value:** 0

#### Measurement

**Group ID:** BG002

**Value:** 1

**Category Title:** Black or African American

#### Measurement

**Group ID:** BG000

**Value:** 5

#### Measurement

**Group ID:** BG001

**Value:** 8

#### Measurement

**Group ID:** BG002

**Value:** 13

**Category Title:** White

#### Measurement

**Group ID:** BG000

**Value:** 0

#### Measurement

**Group ID:** BG001

**Value:** 0

#### Measurement

**Group ID:** BG002

**Value:** 0

**Category Title:** More than one race

#### Measurement

**Group ID:** BG000

**Value:** 0

#### Measurement

**Group ID:** BG001

**Value:** 0

#### Measurement

**Group ID:** BG002

**Value:** 0

**Category Title:** Unknown or Not Reported

**Class Title:** 

**Denomination Units Selected:** 

## Results Section - Baseline Characteristics Module

### Measure 1
**Parameter Type:** COUNT_OF_PARTICIPANTS
**Title:** Age, Categorical
**Unit of Measure:** Participants
### Measure 2
**Parameter Type:** COUNT_OF_PARTICIPANTS
**Title:** Sex: Female, Male
**Unit of Measure:** Participants
### Measure 3
**Parameter Type:** COUNT_OF_PARTICIPANTS
**Title:** Ethnicity (NIH/OMB)
**Unit of Measure:** Participants
### Measure 4
**Parameter Type:** COUNT_OF_PARTICIPANTS
**Title:** Race (NIH/OMB)
**Unit of Measure:** Participants
## Results Section - More Information Module
### Certain Agreement
**PI Sponsor Employee:** True
### Limitations and Caveats
**Description:** 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.
### Point of Contact
**Email:** pamela.guerrerio@nih.gov
**Organization:** National Institute of Allergy and Infectious Diseases
**Phone:** 301-402-9782
**Title:** Pamela Frischmeyer-Guerrerio
## Results Section - Outcome Measures Module
### Outcome Measure 1
### Outcome Measure 2
### Outcome Measure 3
### Outcome Measure 4
### Outcome Measure 5
### Outcome Measure 6
### Outcome Measure 7
### Outcome Measure 8
### Outcome Measure 9
### Outcome Measure 10
### Outcome Measure 11
### Outcome Measure 12
### Outcome Measure 13
## Results Section
### Outcome Measures Module
#### Outcome Measure 1
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 0.016
- **Spread:** 
- **Upper Limit:** 0.383
- **Value:** 0.125
**Title:** 
#### Outcome Measure 2
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 0.016
- **Spread:** 
- **Upper Limit:** 0.383
- **Value:** 0.125
**Title:** 
#### Outcome Measure 3
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 0
- **Spread:** 
- **Upper Limit:** 0.206
- **Value:** 0
**Title:** 
#### Outcome Measure 4
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 0.002
- **Spread:** 
- **Upper Limit:** 0.302
- **Value:** 0.062
**Title:** 
#### Outcome Measure 5
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 0.04
- **Spread:** 
- **Upper Limit:** 0.456
- **Value:** 0.188
**Title:** 
#### Outcome Measure 6
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 0.002
- **Spread:** 
- **Upper Limit:** 0.302
- **Value:** 0.062
**Title:** 
#### Outcome Measure 7
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 0.002
- **Spread:** 
- **Upper Limit:** 0.302
- **Value:** 0.062
**Title:** 
#### Outcome Measure 8
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 0.002
- **Spread:** 
- **Upper Limit:** 0.302
- **Value:** 0.062
**Title:** 
#### Outcome Measure 9
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** -0.134
- **Spread:** 
- **Upper Limit:** 0.383
- **Value:** 0.125
- **Comment:** 
- **Group ID:** OG001
- **Lower Limit:** 0
- **Spread:** 
- **Upper Limit:** 0
- **Value:** 0
**Title:** 
#### Outcome Measure 10
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 0.04
- **Spread:** 
- **Upper Limit:** 0.456
- **Value:** 0.188
**Title:** 
#### Outcome Measure 11
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 0.002
- **Spread:** 
- **Upper Limit:** 0.302
- **Value:** 0.062
**Title:** 
#### Outcome Measure 12
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 0
- **Spread:** 
- **Upper Limit:** 0.206
- **Value:** 0
**Title:** 
#### Outcome Measure 13
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 0
- **Spread:** 
- **Upper Limit:** 0.206
- **Value:** 0
**Title:** 
## Results Section
### Outcome Measures Module
#### Outcome Measure 1
**Description:** 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.
**Dispersion Type:** 95% Confidence Interval
**Parameter Type:** NUMBER
**Population Description:** The analysis included participants who received the active study vaccine in the crossover phase as pre-specified in the protocol to only collect and report data from the active vaccination.
**Reporting Status:** POSTED
**Time Frame:** Within the 3-hour post-vaccine observation period
**Title:** Proportion of Participants Who Had Recurrent Systemic Allergic Reaction to Vaccine
**Type:** PRIMARY
**Unit of Measure:** Proportion of participants
##### Group
**Description:** 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
**ID:** OG000
**Title:** Blinded Active Vaccine 2
#### Outcome Measure 2
**Description:** 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.
**Dispersion Type:** 95% Confidence Interval
**Parameter Type:** NUMBER
**Population Description:** The analysis included participants who received both active study vaccines in the crossover phase and the booster dose in the open label phase
**Reporting Status:** POSTED
**Time Frame:** Within the 3-hour post-vaccine observation period
**Title:** Proportion of Participants Who Had Recurrent Systemic Allergic Reaction to Vaccine
**Type:** PRIMARY
**Unit of Measure:** Proportion of participants
##### Group
**Description:** 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.
**ID:** OG000
**Title:** Open-Label Booster Vaccine
#### Outcome Measure 3
**Description:** Proportion of participants who developed severe 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.

Severe systemic allergic reaction was defined as CoFAR Grade ≥ 3 reaction, regardless of tryptase levels.
**Dispersion Type:** 95% Confidence Interval
**Parameter Type:** NUMBER
**Population Description:** The analysis included participants who received the active study vaccine in the crossover phase as pre-specified in the protocol to only collect and report data from the active vaccination.
**Reporting Status:** POSTED
**Time Frame:** Within the 3-hour post-vaccine observation period
**Title:** Proportion of Participants Who Developed Severe Systemic Allergic Reaction to Vaccine
**Type:** SECONDARY
**Unit of Measure:** Proportion of participants
##### Group
**Description:** 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
**ID:** OG000
**Title:** Blinded Active Vaccine 2
#### Outcome Measure 4
**Description:** Proportion of participants who developed severe 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.

Severe systemic allergic reaction was defined as CoFAR Grade ≥ 3 reaction, regardless of tryptase levels.
**Dispersion Type:** 95% Confidence Interval
**Parameter Type:** NUMBER
**Population Description:** The analysis included those who had a systemic allergic reaction following 1st dose of an mRNA vaccine before study and received both active study active vaccines
**Reporting Status:** POSTED
**Time Frame:** Within the 3-hour post-vaccine observation period
**Title:** Proportion of Participants Who Developed Severe Systemic Allergic Reaction to Vaccine
**Type:** SECONDARY
**Unit of Measure:** Proportion of participants
##### Group
**Description:** 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.
**ID:** OG000
**Title:** Open-Label Booster Vaccine
#### Outcome Measure 5
**Description:** Proportion of participants who developed mild or moderate 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

Mild to moderate systemic allergic reaction was defined as CoFAR Grade 1 or 2 regardless of tryptase level.
**Dispersion Type:** 95% Confidence Interval
**Parameter Type:** NUMBER
**Population Description:** The analysis included participants who received the active study vaccine in the crossover phase as pre-specified in the protocol to only collect and report data from the active vaccination.
**Reporting Status:** POSTED
**Time Frame:** Within the 3-hour post-vaccine observation period
**Title:** Proportion of Participants Who Developed Mild or Moderate Systemic Allergic Reaction Following Active Vaccine Dose
**Type:** SECONDARY
**Unit of Measure:** Proportion of participants
##### Group
**Description:** 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
**ID:** OG000
**Title:** Blinded Active Vaccine 2
#### Outcome Measure 6
**Description:** 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 tr
**Dispersion Type:** 95% Confidence Interval
**Parameter Type:** NUMBER
**Population Description:** The analysis included those who had a systemic allergic reaction following 1st dose of an mRNA vaccine before study and received both active study active vaccines
**Reporting Status:** POSTED
**Time Frame:** Within the 3-hour post-vaccine observation period
**Title:** Proportion of Participants Who Developed Mild or Moderate Systemic Allergic Reaction Following Active Vaccine Dose
**Type:** SECONDARY
**Unit of Measure:** Proportion of participants
##### Group
**Description:** 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.
**ID:** OG000
**Title:** Open-Label Booster Vaccine
#### Outcome Measure 7
**Description:** Proportion of participants with anaphylactic reactions (Levels 1-3) per Brighton Collaboration Criteria to the COVID-19 vaccine after previously demonstrating a systemic allergic reaction to their first full dose of the COVID-19 vaccine. Anaphylaxis was defined using the Brighton Collaboration Criteria as a clinical syndrome characterized by a sudden onset and rapid progression of signs and symptoms involving ≥2 organ systems including skin, cardiovascular, respiratory, gastrointestinal or tryptase elevation (\>upper normal limit). Only specific clinical features from these organ systems meet major and/or minor criteria to provide level of diagnostic certainty for anaphylactic reaction. Reaction meeting levels 1-3 diagnostic certainty are consistent with anaphylaxis
**Dispersion Type:** 95% Confidence Interval
**Parameter Type:** NUMBER
**Population Description:** The analysis included participants who received the active study vaccine in the crossover phase as pre-specified in the protocol to only collect and report data from the active vaccination.
**Reporting Status:** POSTED
**Time Frame:** Within the 3-hour post-vaccine observation period
**Title:** Proportion of Participants Who Developed Anaphylactic Reaction Following Active Dose Delivered
**Type:** SECONDARY
**Unit of Measure:** Proportion of participants
##### Group
**Description:** 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
**ID:** OG000
**Title:** Blinded Active Vaccine 2
#### Outcome Measure 8
**Description:** Proportion of participants with anaphylactic reactions (Levels 1-3) per Brighton Collaboration Criteria to the COVID-19 vaccine after previously demonstrating a systemic allergic reaction to their first full dose of the COVID-19 vaccine. Anaphylaxis was defined using the Brighton Collaboration Criteria as a clinical syndrome characterized by a sudden onset and rapid progression of signs and symptoms involving ≥2 organ systems including skin, cardiovascular, respiratory, gastrointestinal or tryptase elevation (\>upper normal limit). Only specific clinical features from these organ systems meet major and/or minor criteria to provide level of diagnostic certainty for anaphylactic reaction. Reaction meeting levels 1-3 diagnostic certainty are consistent with anaphylaxis.
**Dispersion Type:** 95% Confidence Interval
**Parameter Type:** NUMBER
**Population Description:** The analysis included those who had a systemic allergic reaction following 1st dose of an mRNA vaccine before study and received both active study active vaccines
**Reporting Status:** POSTED
**Time Frame:** Within the 3-hour post-vaccine observation period
**Title:** Proportion of Participants Who Developed Anaphylactic Reaction Following Active Vaccine Dose
**Type:** SECONDARY
**Unit of Measure:** Proportion of participants
##### Group
**Description:** 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.
**ID:** OG000
**Title:** Open-Label Booster Vaccine
#### Outcome Measure 9
**Description:** Participants with recurrent systemic allergic reaction following active vaccine dose in this study compared with reaction in placebo. 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 level. Outcome was calculated as risk difference estimation.
**Dispersion Type:** 95% Confidence Interval
**Parameter Type:** NUMBER
**Population Description:** The analysis included the proportion of participants who had a systemic allergic reaction after receiving the active study vaccine compared to the proportion who had a systemic allergic reaction after receiving placebo during the crossover phase of the study.
**Reporting Status:** POSTED
**Time Frame:** Within the 3-hour post-vaccine observation period
**Title:** Proportion of Participants Who Had Recurrent Systemic Allergic Reaction Following Active Vaccine Dose Compared With Rate of Reaction in Placebo
**Type:** SECONDARY
**Unit of Measure:** Proportion of participants
##### Group
**Description:** 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 in the crossover phase of the study.
**ID:** OG000
**Title:** Blinded Active Vaccine 2
##### Group
**Description:** 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 placebo (0.3 mL normal saline) intramuscularly in the crossover phase of the study.
**ID:** OG001
**Title:** Placebo
#### Outcome Measure 10
**Description:** Proportion of participants with less severe allergic reaction to the vaccine dose in this study than recorded reaction to the first full COVID-19 vaccine dose (pre-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.
**Dispersion Type:** 95% Confidence Interval
**Parameter Type:** NUMBER
**Population Description:** The analysis included participants who received the active study vaccine in the crossover phase as pre-specified in the protocol to only collect and report data from the active vaccination.
**Reporting Status:** POSTED
**Time Frame:** Within the 3-hour post-vaccine observation period
**Title:** Proportion of Participants With Less Severe Allergic Reaction to the Vaccine Dose Delivered in This Study Than Recorded Reaction to the First Full COVID-19 Vaccine Dose
**Type:** SECONDARY
**Unit of Measure:** Proportion of participants
##### Group
**Description:** 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
**ID:** OG000
**Title:** Blinded Active Vaccine 2
#### Outcome Measure 11
**Description:** Proportion of participants with less severe allergic reaction to the vaccine dose in this study than recorded reaction to the first full COVID-19 vaccine dose (pre-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.
**Dispersion Type:** 95% Confidence Interval
**Parameter Type:** NUMBER
**Population Description:** The analysis included those who had a systemic allergic reaction following 1st dose of an mRNA vaccine before study and received both active study active vaccines (blinded and open-label)
**Reporting Status:** POSTED
**Time Frame:** Within the 3-hour post-vaccine observation period
**Title:** Proportion of Participants With Less Severe Allergic Reaction to the Vaccine Dose Delivered in This Study Than Recorded Reaction to the First Full COVID-19 Vaccine Dose
**Type:** SECONDARY
**Unit of Measure:** Proportion of participants
##### Group
**Description:** 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.
**ID:** OG000
**Title:** Open-Label Booster Vaccine
#### Outcome Measure 12
**Description:** "Proportion of participants with more severe allergic reaction to the vaccine dose in this study than recorded reaction to the first full COVID-19 vaccine dose (pre-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.
**Dispersion Type:** 95% Confidence Interval
**Parameter Type:** NUMBER
**Population Description:** The analysis included participants who received the active study vaccine in the crossover phase as pre-specified in the protocol to only collect and report data from the active vaccination.
**Reporting Status:** POSTED
**Time Frame:** Within the 3-hour post-vaccine observation period
**Title:** Proportion of Participants With More Severe Systemic Allergic Reaction to the Vaccine Dose Delivered in This Study Than Recorded Reaction to the First Full Vaccine Dose
**Type:** SECONDARY
**Unit of Measure:** Proportion of participants
##### Group
**Description:** 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
**ID:** OG000
**Title:** Blinded Active Vaccine 2
#### Outcome Measure 13
**Description:** "Proportion of participants with more severe allergic reaction to the vaccine dose in this study than recorded reaction to the first full COVID-19 vaccine dose (pre-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.
**Dispersion Type:** 95% Confidence Interval
**Parameter Type:** NUMBER
**Population Description:** The analysis included those who had a systemic allergic reaction following 1st dose of an mRNA vaccine before study and received both active study active vaccines (blinded and open-label)
**Reporting Status:** POSTED
**Time Frame:** Within the 3-hour post-vaccine observation period
**Title:** Proportion of Participants With More Severe Systemic Allergic Reaction to the Vaccine Dose Delivered in This Study Than Recorded Reaction to the First Full Vaccine Dose
**Type:** SECONDARY
**Unit of Measure:** Proportion of participants
##### Group
**Description:** 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.
**ID:** OG000
**Title:** Open-Label Booster Vaccine
### Participant Flow Module
#### Group
**Description:** 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.
**ID:** FG000
**Title:** Blinded Active Vaccine 2
#### Group
**Description:** 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.
**ID:** FG001
**Title:** Blinded Placebo
#### Group
**Description:** 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.
**ID:** FG002
**Title:** Open-Label Booster Vaccine
#### Period
**Title:** First Period of Crossover
##### Milestone
**Type:** STARTED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 8
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 8
###### Achievement
**Group ID:** FG002
**Number of Subjects:** 0
##### Milestone
**Type:** COMPLETED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 8
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 8
###### Achievement
**Group ID:** FG002
**Number of Subjects:** 0
##### Milestone
**Type:** NOT COMPLETED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 0
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 0
###### Achievement
**Group ID:** FG002
**Number of Subjects:** 0
#### Period
**Title:** Washout Period
##### Milestone
**Type:** STARTED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 8
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 8
###### Achievement
**Group ID:** FG002
**Number of Subjects:** 0
##### Milestone
**Type:** COMPLETED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 8
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 8
###### Achievement
**Group ID:** FG002
**Number of Subjects:** 0
##### Milestone
**Type:** NOT COMPLETED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 0
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 0
###### Achievement
**Group ID:** FG002
**Number of Subjects:** 0
#### Period
**Title:** Second Period of Crossover
##### Milestone
**Type:** STARTED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 8
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 8
###### Achievement
**Group ID:** FG002
**Number of Subjects:** 0
##### Milestone
**Type:** COMPLETED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 8
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 8
###### Achievement
**Group ID:** FG002
**Number of Subjects:** 0
##### Milestone
**Type:** NOT COMPLETED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 0
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 0
###### Achievement
**Group ID:** FG002
**Number of Subjects:** 0
#### Period
**Title:** Open Label
##### Milestone
**Type:** STARTED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 0
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 0
###### Achievement
**Group ID:** FG002
**Number of Subjects:** 16
##### Milestone
**Type:** COMPLETED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 0
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 0
###### Achievement
**Group ID:** FG002
**Number of Subjects:** 16
##### Milestone
**Type:** NOT COMPLETED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 0
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 0
###### Achievement
**Group ID:** FG002
**Number of Subjects:** 0
**Pre-Assignment Details:** Three participants withdrew prior to start of study. One participant was ineligible due to partial 2nd vaccine dose pre-enrollment outside of the study
**Has Results:** True