A randomized double-blinded trial to assess recurrence of systemic allergic reactions following COVID-19 mRNA vaccination

Muhammad B Khalid; Ellen Zektser; Eric Chu; Min Li; Joanna Utoh; Patrick Ryan; Hanna S Loving; Roa Harb; Robbie Kattappuram; Lindsay Chatman; Stella Hartono; Estefania Claudio-Etienne; Guangping Sun; Edward P Feener; Zhongbo Li; Samuel K Lai; Quang Le; Lawrence B Schwartz; Jonathan J Lyons; Hirsh Komarow; Zhao-Hua Zhou; Haniya Raza; Maryland Pao; Karen Laky; Steven M Holland; Erica Brittain; Pamela A Frischmeyer-Guerrerio

doi:10.1016/j.jaci.2024.03.001

A randomized double-blinded trial to assess recurrence of systemic allergic reactions following COVID-19 mRNA vaccination

J Allergy Clin Immunol. 2024 Mar 7:S0091-6749(24)00236-7. doi: 10.1016/j.jaci.2024.03.001. Online ahead of print.

Authors

Muhammad B Khalid¹, Ellen Zektser¹, Eric Chu², Min Li¹, Joanna Utoh¹, Patrick Ryan³, Hanna S Loving⁴, Roa Harb⁴, Robbie Kattappuram⁵, Lindsay Chatman¹, Stella Hartono¹, Estefania Claudio-Etienne¹, Guangping Sun¹, Edward P Feener⁶, Zhongbo Li⁷, Samuel K Lai⁷, Quang Le⁸, Lawrence B Schwartz⁸, Jonathan J Lyons⁹, Hirsh Komarow¹⁰, Zhao-Hua Zhou¹¹, Haniya Raza³, Maryland Pao³, Karen Laky¹, Steven M Holland¹², Erica Brittain¹³, Pamela A Frischmeyer-Guerrerio¹⁴

Affiliations

¹ Food Allergy Research Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
² Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, Md.
³ Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health, Bethesda, Md.
⁴ Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Md.
⁵ Investigational Drug Management and Research Section, Clinical Center, National Institutes of Health, Bethesda, Md.
⁶ KalVista Pharmaceuticals, Cambridge, Mass.
⁷ Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina Chapel Hill, Chapel Hill, NC.
⁸ Department of Internal Medicine, Division of Rheumatology, Allergy, and Immunology, Virginia Commonwealth University, Richmond, Va.
⁹ Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
¹⁰ Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
¹¹ Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Md.
¹² Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
¹³ Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
¹⁴ Food Allergy Research Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: pamela.guerrerio@nih.gov.

PMID: 38460680
DOI: 10.1016/j.jaci.2024.03.001

Abstract

Background: Systemic allergic reactions (sARs) following coronavirus disease 2019 (COVID-19) mRNA vaccines were initially reported at a higher rate than after traditional vaccines.

Objective: We aimed to evaluate the safety of revaccination in these individuals and to interrogate mechanisms underlying these reactions.

Methods: In this randomized, double-blinded, phase 2 trial, participants aged 16 to 69 years who previously reported a convincing sAR to their first dose of COVID-19 mRNA vaccine were randomly assigned to receive a second dose of BNT162b2 (Comirnaty) vaccine and placebo on consecutive days in a blinded, 1:1 crossover fashion at the National Institutes of Health. An open-label BNT162b2 booster was offered 5 months later if the second dose did not result in severe sAR. None of the participants received the mRNA-1273 (Spikevax) vaccine during the study. The primary end point was recurrence of sAR following second dose and booster vaccination; exploratory end points included biomarker measurements.

Results: Of 111 screened participants, 18 were randomly assigned to receive study interventions. Eight received BNT162b2 second dose followed by placebo; 8 received placebo followed by BNT162b2 second dose; 2 withdrew before receiving any study intervention. All 16 participants received the booster dose. Following second dose and booster vaccination, sARs recurred in 2 participants (12.5%; 95% CI, 1.6 to 38.3). No sAR occurred after placebo. An anaphylaxis mimic, immunization stress-related response (ISRR), occurred more commonly than sARs following both vaccine and placebo and was associated with higher predose anxiety scores, paresthesias, and distinct vital sign and biomarker changes.

Conclusions: Our findings support revaccination of individuals who report sARs to COVID-19 mRNA vaccines. Distinct clinical and laboratory features may distinguish sARs from ISRRs.

Keywords: Anaphylaxis; COVID-19; ISRR; PEG; allergic reaction; immunization stress-related response; mRNA; vaccine.