Maintaining Safety with SARS-CoV-2 Vaccines

Review article by Mariana C. Castells, M.D., Ph.D., and Elizabeth J. Phillips, M.D. in The NEW ENGLAND JOURNAL of  MEDICINE 

To date, the development of mRNA vaccines for the prevention of infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a success story, with no serious concerns identified in the ongoing phase 3 clinical trials. Minor local side effects such as pain, redness, and swelling have been observed more frequently with the vaccines than with placebo. Systemic symptoms such as fever, fatigue, headache, and muscle and joint pain have also been somewhat more common with the vaccines than with placebo, and most have occurred during the first 24 to 48 hours after vaccination. In the phase 1–3 clinical trials of the Pfizer–BioNTech and Moderna mRNA vaccines, potential participants with a history of an allergic reaction to any component of the vaccine were excluded. The Pfizer–BioNTech studies also excluded participants with a history of severe allergy associated with any vaccine (see the protocols of the two trials, available with the full text of the articles at NEJM.org, for full exclusion criteria). Hypersensitivity adverse events were equally represented in the placebo (normal saline) and vaccine groups in both trials.¹

The Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom was the first to authorize emergency use of the Pfizer–BioNTech mRNA vaccine. On December 8, 2020, within 24 hours after the start of the U.K. mass vaccination program for health care workers and elderly adults, the program reported probable cases of anaphylaxis in two women, 40 and 49 years of age, who had known food and drug allergies and were carrying auto-injectable epinephrine. On December 11, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for the Pfizer–BioNTech mRNA vaccine, and general vaccination of health care workers was started on Monday, December 14. On December 15, a 32-year-old female health care worker in Alaska who had no known allergies presented with an anaphylactic reaction within 10 minutes after receiving the first dose of the vaccine. The participants who had these initial three reported cases of anaphylaxis would not have been excluded on the basis of their histories from the mRNA vaccine clinical trials. Since the index case in Alaska, several more cases of anaphylaxis associated with the Pfizer mRNA vaccine have been reported in the United States after vaccination of almost 2 million health care workers, and the incidence of anaphylaxis associated with the Pfizer SARS-CoV-2 mRNA vaccine appears to be approximately 10 times as high as the incidence reported with all previous vaccines, at approximately 1 in 100,000, as compared 1 in 1,000,000, the known and stable incidence of anaphylaxis associated with other vaccines. The EUA for the Moderna mRNA vaccine was issued on December 18, and it is currently too soon to know whether a similar signal for anaphylaxis will be associated with that vaccine; however, at this time a small number of potential cases of anaphylaxis have been reported, including one case on December 24 in Boston in a health care worker with shellfish allergy who was carrying auto-injectable epinephrine.

In response to the two cases of anaphylaxis in the United Kingdom, the MHRA issued a pause on vaccination with the Pfizer–BioNTech SARS-CoV-2 mRNA vaccine, to exclude any person with a history of anaphylactic reaction to any food, drug, or vaccine. The Centers for Disease Control and Prevention (CDC) has issued advice pertaining to administration of either the first or the second dose of the Pfizer–BioNTech or Moderna mRNA vaccine, recommending exclusion of any person who has a history of a severe or immediate (within 4 hours) allergic reaction associated with any of the vaccine components, including polyethylene glycol (PEG) and PEG derivatives such as polysorbates.

Anaphylaxis is a serious multisystem reaction with rapid onset and can lead to death by asphyxiation, cardiovascular collapse, and other complications. It requires prompt recognition and treatment with epinephrine to halt the rapid progression of life-threatening symptoms. The cause of anaphylactic reactions is the activation of mast cells through antigen binding and cross-linking of IgE; the symptoms result from the tissue response to the release of mediators such as histamine, proteases, prostaglandins, and leukotrienes and typically include flushing, hives, laryngeal edema, wheezing, nausea, vomiting, tachycardia, hypotension, and cardiovascular collapse. Patients become IgE-sensitized by previous exposure to antigens. Reactions that resemble the clinical signs and symptoms of anaphylaxis, previously known as anaphylactoid reactions, are now referred to as non-IgE–mediated reactions because they do not involve IgE. They manifest the same clinical features and response to epinephrine, but they occur by direct activation of mast cells and basophils, complement activation, or other pathways and can occur on first exposure. Tryptase is typically elevated in blood in IgE-mediated anaphylaxis and, to a lesser extent, in non–IgE-mediated mast-cell activation, a feature that identifies mast cells as the sources of inflammatory mediators. Prick and intradermal skin testing and analysis of blood samples for serum IgE are used to identify the specific drug culprit, although the tests lack 100% negative predictive value. The clinical manifestations of the two U.K. cases and the one U.S. case fit the description of anaphylaxis: they occurred within minutes after the injections, symptoms were typical, and all responded to epinephrine. The occurrence on first exposure is not typical of IgE-mediated reactions; however, preexisting sensitization to a component of the vaccine could account for this observation.

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