Peer Reviewed


mRNA COVID-19 Vaccines and Anaphylaxis

Chioma M. Enweasor, MD1 • Samuel Louie, MD2

1Loma Linda University, California
2University of California, Davis, California

Enweasor CM, Louie S. Lies, damned lies, and anaphylaxis. Consultant. Published online August 5, 2021. doi:10.25270/con.2021.08.00004

Dr Louie reports serving as a speaker and consultant for AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Regeneron, and Sanofi Genzyme.

Samuel Louie, MD, UC Davis Medical Center, 4150 V Street, Ste 3400, Sacramento, CA 95817 (


To read the full article on anaphylaxis, click here.


The classical explanation of anaphylaxis is that in genetically susceptible patients, subsequent re-exposure to an antigen that has become an allergen leads to crosslinking of immunoglobulin E (IgE) antibodies bound to FCeR1 receptors on mast cells and basophils. Mast cells and basophils degranulate once these antibodies crosslink on the cell surface releasing histamine, tryptase, and proteases that can, but not always, culminate in anaphylaxis.1 However, this limited view fails to explain why anaphylaxis occurs upon first exposure (eg, first injection of the mRNA COVID-19 vaccine, first infusion of rocuronium under general anesthesia, or first dose of chemotherapy).

From December 14, 2020, to December 23, 2020, monitoring by the Centers for Disease Control and Prevention (CDC) Vaccine Adverse Event Reporting System (VAERS) detected 21 cases of anaphylaxis after administration of a reported 1,893,360 first doses of the Pfizer-BioNTech COVID-19 vaccine (11.1 cases per million doses); 71% of these occurred within 15 minutes of vaccination.2 The incidence of anaphylaxis and severe hypersensitivity reactions with the Pfizer mRNA COVID-19 vaccine was 4.7 cases per million doses administered (0.005% incidence).2 With the Moderna vaccine, 2.5 cases per million doses were reported (0.0025% incidence).2 There were no apparent clinical differences between anaphylaxis cases with symptom onset within 30 minutes and those with symptom onset after 30 minutes (a 15-minute post-vaccination observation period was recommended for all persons and a 30-minute period was recommended for those with a history of certain allergic reactions).

Of the 66 case reports identified by the CDC’s VAERS, 21 (32%) noted a prior history of anaphylaxis from other exposures (eg, from vaccines like rabies, influenza A, seasonal influenza, unspecified), contrast media (eg, gadolinium-based, iodine-based, unspecified intravenous), unspecified infusions, sulfonamide medications, penicillin, prochlorperazine, latex, walnuts, unspecified tree nuts, jellyfish stings, and unspecified exposures. In 61 cases (92%), patients had received epinephrine as part of emergency treatment.2

Current evidence suggests that anaphylaxis after administration of an mRNA COVID-19 vaccine may be induced by SARS-CoV-2 spike glycoprotein and/or by stabilizer (ie, sucrose or polyethylene glycol [PEG]) that interact with IgE.3 Avoiding a, mRNA COVID-19 vaccine is recommended if a patient is allergic to PEG or polysorbate because of the risk of anaphylaxis. PEG and polysorbate are closely related to each other. PEG is an ingredient in the mRNA vaccines, and polysorbate is an ingredient in the Janssen vaccine. Prior allergies to shellfish, egg, and milk were not considered contraindications to the mRNA vaccines.4

The incidence of anaphylaxis with mRNA vaccines can be compared to data from the Vaccine Safety Datalink, where the rates of anaphylaxis after vaccination in children and adults from January 2009 through December 2011 were collected with diagnostic and procedure codes.5 A total of 33 confirmed vaccine-triggered anaphylaxis cases had occurred after 25,173,965 vaccine doses. Skin eruptions and respiratory distress dominated the clinical presentation of anaphylaxis in this group. The rate of anaphylaxis was 1.31 per million vaccine doses, which included vaccines for influenza and tetanus, diphtheria, pertussis.5 Vaccine-specific rates included 1.35 per million doses for the inactivated trivalent influenza vaccine and 1.83 per million doses for inactivated monovalent influenza vaccine. Nearly half of the patients had a prior history of asthma, whereas food and antibiotic allergies were reported in patients without a prior diagnosis of asthma.5

The onset of symptoms among cases was within 30 minutes (8 cases), 30 to less than 120 minutes (8 cases), 2 to less than 4 hours (10 cases), 4 to 8 hours (2 cases), the next day (1 case), and not documented (4 cases).5 The incidence of anaphylaxis did not vary significantly by age, and there was a nonsignificant female predominance. Only 45% of cases were treated with epinephrine compared with 85% with antihistamines and 52% with corticosteroids. No deaths had occurred, but 1 patient was hospitalized. A total of 85% of patients reported atopy, but 15% of cases were referred to an allergist after anaphylaxis.5

Anaphylaxis after vaccination is rare for all vaccines, including mRNA vaccines. Despite its rarity, anaphylaxis is a potentially life-threatening hypersensitivity reaction that clinicians need to be prepared to treat with epinephrine.


1. Finkelman FD, Khodoun MV, Strait R. Human IgE-independent systemic anaphylaxis. J Allergy Clin Immunol. 2016;137(6):1674-1680.

2. Shimabukuro TT, Cole M, Su JR. Reports of anaphylaxis after receipt of mRNA COVID-19 vaccines in the US-December 14, 2020-January 18, 2021. JAMA. 2021;325(11):1101-1102.

3. Selvaraj G, Kaliamurthi S, Peslherbe GH, Wei DQ. Are the allergic reactions of COVID-19 vaccines caused by mRNA constructs or nanocarriers? Immunological Insights. Interdiscip Sci. 2021;13(2):344-347.

4. Contraindications. Interim clinical considerations for use of COVID-19 vaccines currently authorized in the United States. Updated July 16, 2021. Accessed July 30, 2021.

5. McNeil MM, Weintraub ES, Duffy J, et al. Risk of anaphylaxis after vaccination in children and adults. J Allergy Clin Immunol. 2016;137(3):868-878.