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
Condition: Systemic Allergic Reaction
MeSH terms: COVID-19; Hypersensitivity
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Pfizer-BioNTech COVID-19 Vaccine (Comirnaty); Placebo; Pfizer-BioNTech COVID-19 Vaccine, Bivalent
Intervention type(s): Biological; Other; Biological
Intervention description(s): mRNA vaccine for the prevention of COVID-19. Single dose (0.3mL) via IM.; 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.; mRNA vaccine booster bivalent (Original and Omicron BA.4/BA.5) for the prevention of COVID-19. Single dose (0.3mL) via IM.
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: polyethylene glycol (PEG); Pfizer-BioNTech COVID-19 vaccine; Moderna Covid-19 vaccine; Consortium for Food Allergy Research (CoFAR); SARS-CoV-2; Comirnaty